Arterioskleroza / miażdżyca – Patofizjologia i mechanizm

Arterioskleroza / miażdżyca
Patofizjologia i mechanizm

Arterioskleroza to ogólne stwardnienie i utrata elastyczności tętnic, podczas gdy miażdżyca (atherosclerosis) jest jej specyficznym typem, charakteryzującym się tworzeniem blaszek miażdżycowych w błonie wewnętrznej dużych i średnich tętnic. Miażdżyca jest chorobą wieloczynnikową, inicjowaną przez dysfunkcję śródbłonka, akumulację lipoprotein LDL, ich utlenianie oraz aktywację procesów zapalnych. Kluczowe mechanizmy patogenetyczne obejmują aktywację śródbłonka, rekrutację monocytów, przekształcenie ich w makrofagi i komórki piankowate, a także proliferację komórek mięśni gładkich (VSMCs) i tworzenie czapeczki włóknistej. Proces ten prowadzi do powstania blaszki miażdżycowej, która może być stabilna lub niestabilna, z ryzykiem pęknięcia i powikłań zakrzepowych. Warto podkreślić rolę stresu oksydacyjnego, reaktywnych form tlenu (ROS), cytokin prozapalnych (np. IL-1, TNF-α), czynników wzrostu oraz czynników transkrypcyjnych NF-κB i HIF-1 w progresji choroby.

Arterioskleroza / miażdżyca – wprowadzenie

Arterioskleroza to zaburzenie charakteryzujące się pogrubieniem i utratą elastyczności ścian tętniczych. Miażdżyca (atherosclerosis) jest specyficznym rodzajem arteriosklerozy i charakteryzuje się rozwojem blaszek miażdżycowych w błonie wewnętrznej dużych i średnich tętnic¹. Chociaż te dwa terminy są czasami używane zamiennie, istnieje między nimi różnica – arterioskleroza to ogólne stwardnienie i sztywnienie tętnic, podczas gdy miażdżyca odnosi się konkretnie do gromadzenia się tłuszczów, cholesterolu i innych substancji w ścianach tętnic, tworząc blaszkę miażdżycową².

Miażdżyca jest głównym czynnikiem ryzyka chorób sercowo-naczyniowych (CVD), które są wiodącą przyczyną zgonów na całym świecie. Jest ona inicjowana przez aktywację śródbłonka, a następnie kaskadę zdarzeń (akumulacja lipidów, elementów włóknistych i zwapnienia), co powoduje zwężenie naczyń i aktywację szlaków zapalnych. Powstała blaszka miażdżycowa, wraz z tymi procesami, prowadzi do powikłań sercowo-naczyniowych³⁴.

Etiopatogeneza miażdżycy

Miażdżyca jest chorobą wieloczynnikową indukowaną przez wpływ różnych czynników ryzyka na odpowiednie podłoże genetyczne. Wiele czynników ryzyka, takich jak hipercholesterolemia, zmodyfikowane lipoproteiny, nadciśnienie, cukrzyca, infekcje i palenie tytoniu, zostało zidentyfikowanych w rozwoju miażdżycy⁵.

Istnieje kilka głównych hipotez wyjaśniających patogenezę miażdżycy:

Hipoteza odpowiedzi na uraz – opiera się na koncepcji, że pierwotną przyczyną miażdżycy jest uraz śródbłonka tętniczego wywołany przez różne czynniki, w tym palenie, stres mechaniczny, utlenione LDL, homocysteinę, zdarzenia immunologiczne, toksyny, wirusy itp.⁶
Hipoteza utlenionego LDL – postuluje, że LDL utlenione przez różne czynniki, w tym komórki śródbłonka, makrofagi i komórki mięśni gładkich ściany tętnic, odgrywa kluczową rolę w rozwoju miażdżycy⁷
Hipoteza zapalna – miażdżyca jest chorobą zapalną, ponieważ nowsze badania wykazały fundamentalną rolę zapalenia w pośredniczeniu we wszystkich etapach tej choroby, od inicjacji przez progresję, aż po zakrzepowe powikłania miażdżycy⁸

Patofizjologia inicjacji procesu miażdżycowego

Rozwój miażdżycy prawdopodobnie wymaga lipoprotein o niskiej gęstości (LDL), cząsteczek przenoszących cholesterol przez krew⁹. Zatrzymanie lipoprotein zawierających apolipoproteinę B w ścianie tętnic jest kluczowym wydarzeniem inicjującym patobiologię miażdżycy¹⁰.

Proces inicjacji miażdżycy rozpoczyna się od dysfunkcji śródbłonka. Kiedy komórki śródbłonka tracą zdolność do utrzymania homeostazy, ściany naczyń są predysponowane do skurczu naczyń, infiltracji lipidów, adhezji leukocytów, aktywacji płytek krwi i stresu oksydacyjnego. Razem wywołują one odpowiedź zapalną, która jest uważana za pierwszy krok w tworzeniu blaszki miażdżycowej: pasmo tłuszczowe¹¹¹².

Siły hemodynamiczne stanowią lokalny czynnik ryzyka aterogenezy, ponieważ sprzyjają dysfunkcji śródbłonka¹³¹⁴. Nielaminarne lub turbulentne przepływy krwi (np. w punktach rozgałęzienia drzewa tętniczego) prowadzą do dysfunkcji śródbłonka i hamują śródbłonkową produkcję tlenku azotu, silnego wazodylatatora i cząsteczki przeciwzapalnej. Taki przepływ krwi stymuluje również komórki śródbłonka do produkcji cząsteczek adhezyjnych, które rekrutują i wiążą komórki zapalne¹⁵.

Dysfunkcja śródbłonka jest również wyjaśniana przez zmniejszenie biodostępności NO. NO jest syntetyzowany z L-argininy w komórkach śródbłonka w reakcji katalizowanej przez eNOS i dyfunduje przez błony komórkowe, docierając do tkanki mięśniowej gładkiej ściany tętnicy. NO promuje relaksację włókien mięśni gładkich, znaną jako zależna od śródbłonka wazodylatacja, i jest uważany za cząsteczkę athero-ochronną, ponieważ przeciwdziała aterogenezie i jej powikłaniom¹⁶¹⁷.

Patofizjologia rozwoju blaszki miażdżycowej

Akumulacja LDL w osoczu sprzyja transendotelialnej infiltracji krążących LDL do błony wewnętrznej¹⁸. Po uszkodzeniu śródbłonka cząsteczki LDL przedostają się do przestrzeni podśródbłonkowej i ulegają utlenieniu, co jest ułatwione przez brak ochronnych antyoksydantów osocza, takich jak tokoferol, askorbinian, moczany, apolipoproteiny czy albumina surowicy¹⁹.

Utlenione LDL są kluczowymi składnikami zapalnymi, które promują rozwój blaszki miażdżycowej, ponieważ zawierają utlenione lipidy i produkty pochodzące z ich degradacji, które przyczyniają się do patofizjologii choroby²⁰. Utlenione LDL powodują aktywację śródbłonka, co prowadzi do selektywnej rekrutacji monocytów do błony wewnętrznej²¹.

Monocyty w podśródbłonku przekształcają się w makrofagi. Lipidy we krwi, szczególnie cholesterol lipoprotein o niskiej gęstości (LDL) i cholesterol lipoprotein o bardzo niskiej gęstości (VLDL), wiążą się również z komórkami śródbłonka i są utleniane w podśródbłonku²².

Wychwyt utlenionych lipidów i przekształcenie makrofagów w komórki piankowate bogate w lipidy prowadzi do typowych wczesnych zmian miażdżycowych zwanych pasemkami tłuszczowymi²³. Makrofagi produkują prozapalne cytokiny, które rekrutują migrację komórek mięśni gładkich z błony środkowej oraz dalej przyciągają i stymulują wzrost makrofagów²⁴.

W rezultacie powstaje podśródbłonkowa blaszka włóknista z czapeczką włóknistą, zbudowana z komórek mięśni gładkich błony wewnętrznej otoczonych tkanką łączną oraz lipidami wewnątrzkomórkowymi i zewnątrzkomórkowymi²⁵. Proces podobny do tworzenia kości powoduje zwapnienie w obrębie blaszki²⁶.

Patofizjologia powikłań miażdżycowych

Blaszki miażdżycowe mogą być stabilne lub niestabilne²⁷:

Stabilne blaszki – ulegają regresji, pozostają statyczne lub powoli rosną przez kilka dekad, aż mogą spowodować zwężenie lub niedrożność²⁸
Niestabilne blaszki – są podatne na spontaniczną erozję, pęknięcie lub rozerwanie, powodując ostry zakrzep, niedrożność i zawał na długo przed wywołaniem hemodynamicznie znaczącego zwężenia²⁹

Wytrzymałość czapeczki włóknistej i jej odporność na pękanie zależą od względnej równowagi odkładania i degradacji kolagenu³⁰. Pęknięcie blaszki obejmuje wydzielanie metaloproteinaz, katepsyn i kolagenaz przez aktywowane makrofagi w blaszce³¹. Enzymy te trawią czapeczkę włóknistą, szczególnie na krawędziach, powodując jej ścieńczenie i ostatecznie pęknięcie³². Cytokiny hamują komórki mięśni gładkich przed syntezą i odkładaniem kolagenu, który normalnie wzmacnia blaszkę³³.

Po pęknięciu blaszki jej zawartość jest eksponowana na krążącą krew, wyzwalając zakrzepicę; makrofagi również stymulują zakrzepicę, ponieważ zawierają czynnik tkankowy, który promuje generację trombiny in vivo³⁴.

Blaszka jest uważana za podatną, gdy zmiana wykazuje duży rdzeń martwicy, cienką czapeczkę włóknistą i zwiększoną odpowiedź zapalną z powodu ciągłego narażenia na środowisko pro-aterogenne³⁵. Gdy blaszka pęka lub ulega pęknięciu, przestrzeń podśródbłonkowa jest eksponowana na krew, wyzwalając proces krzepnięcia w celu pokrycia rany³⁶.

Molekularne mechanizmy miażdżycowe

W patogenezie miażdżycy zaangażowanych jest wiele złożonych mechanizmów molekularnych, które prowadzą do rozwoju i progresji tej choroby³⁷³⁸.

Rola zapalenia w patogenezie miażdżycy

Miażdżyca jest obecnie uznawana za chorobę zapalną. Zapalenie odgrywa kluczową rolę na wszystkich etapach miażdżycy, od inicjacji przez progresję, aż po powikłania zakrzepowe³⁹.

Monocyty/makrofagi są w centrum napędzania zapalenia blaszki w miażdżycy, z szerokimi i skomplikowanymi mechanizmami molekularnymi, które nie są w pełni rozszyfrowane⁴⁰. Nadmierne zatrzymanie lub utlenienie LDL w podśródbłonkowej warstwie tętnic prowokuje powstawanie monocytów z komórek progenitorowych w szpiku kostnym i ich późniejsze uwalnianie do krążenia⁴¹.

Zapalne makrofagi uwalniają chemokiny/cytokiny, które promują zapalenie blaszki⁴². Ze względu na środowisko zapalne blaszki, aktywowane są czynniki prokoagulacyjne i zwiększa się produkcja fibryny⁴³.

Identyfikacja aterogenezy jako aktywnego procesu, a nie biernej choroby magazynowania cholesterolu, uwydatniła ważne szlaki zapalne, molekularne i komórkowe⁴⁴. Zapalenie rozpoczyna się od inflammasomów, które są wrodzonymi immunologicznymi kompleksami sygnalizacyjnymi, będącymi znaczącymi modulatorami produkcji cytokin rodziny IL-1 w miażdżycy, przyczyniając się do naczyniowej odpowiedzi zapalnej, która napędza rozwój i progresję miażdżycy⁴⁵.

Rola stresu oksydacyjnego

Stres oksydacyjny odgrywa kluczową rolę w patogenezie miażdżycy. Hipercholesterolemia generuje reaktywne formy tlenu (ROS)⁴⁶. Reakcje utleniania prowadzą do powstawania utlenionych LDL (oxLDL), które są kluczowymi składnikami zapalnymi w rozwoju blaszki miażdżycowej⁴⁷.

Hipercholesterolemia zwiększa aktywność enzymów produkujących utleniacze, oksydazy NADPH i oksydazy ksantynowej⁴⁸. Hipercholesterolemia aktywuje także czynnik jądrowy NF-κB. Krążący NF-κB jest podwyższony w rodzinnej hipercholesterolemii⁴⁹.

Utlenienie LDL promuje jego wychwyt przez makrofagi w warstwie wewnętrznej⁵⁰. Wiązanie i wychwyt oxLDL przez CD36 indukuje aktywację osi wimentyna/FAK/NF-κB w makrofagach, prowadząc do uwalniania cytokin i zapalenia⁵¹.

Rola niedotlenienia (hipoksji)

Niedotlenienie odgrywa istotną rolę w patogenezie miażdżycy. Aktywacja HIF-1 indukowana hipoksją w makrofagach może prowadzić do downregulacji PPAR-γ, napędzając tym samym zapalenie blaszki poprzez reaktywację genów prozapalnych i represję genów przeciwzapalnych⁵².

Ogólnie, te odkrycia sugerowałyby, że hipoksja aktywuje mTORC1 w makrofagach, prowadząc do zapalenia blaszki za pośrednictwem szlaków sygnałowych NF-κB i HIF-1⁵³.

Progresja miażdżycy – etapy rozwoju

Miażdżyca rozwija się jako wynik ciągłego procesu, który obejmuje aktywację śródbłonka, akumulację lipidów, tworzenie blaszki miażdżycowej, przebudowę naczyń i ostateczne zwężenie światła naczynia krwionośnego⁵⁴.

Etapy miażdżycy zachodzą przez wiele lat i obejmują⁵⁵:

Uszkodzenie śródbłonka i odpowiedź immunologiczna – Uszkodzenie śródbłonka wyzwala procesy chemiczne, które powodują przemieszczanie się białych krwinek do miejsca urazu. Komórki te gromadzą się i prowadzą do zapalenia w obrębie tętnicy.
Tworzenie pasma tłuszczowego – Jest to pierwszy widoczny znak miażdżycy. To żółte pasmo lub plama z martwych komórek piankowatych w miejscu uszkodzenia śródbłonka. W tym przypadku komórki piankowate to białe krwinki, które pochłaniają cholesterol, aby się go pozbyć. Ciągła aktywność komórek piankowatych powoduje dalsze uszkodzenie śródbłonka.
Wzrost blaszki – Martwe komórki piankowate i inne szczątki nadal się gromadzą, przekształcając pasmo tłuszczowe w większy fragment blaszki. Czapeczka włóknista (zbudowana z komórek mięśni gładkich) tworzy się nad blaszką. Ta czapeczka zapobiega odrywaniu się fragmentów blaszki do krwiobiegu. W miarę wzrostu blaszki stopniowo zwęża się światło tętnicy, więc jest mniej miejsca na przepływ krwi.
Pęknięcie lub erozja blaszki – Na tym etapie w tętnicy tworzy się skrzep krwi z powodu pęknięcia blaszki lub jej erozji. Pęknięcie blaszki następuje, gdy pęka czapeczka włóknista pokrywająca blaszkę. Przy erozji blaszki czapeczka włóknista pozostaje nienaruszona, ale komórki śródbłonka wokół blaszki ulegają starciu. Oba zdarzenia prowadzą do powstania skrzepu krwi. Skrzep blokuje przepływ krwi i może prowadzić do zawału serca lub udaru mózgu.

Powstawanie jądra martwicy

Jądro martwicze stanowi centrum blaszek miażdżycowych. Pokryte czapeczką włóknistą, jądro martwicze składa się z bogatego w lipidy hipokomórkowego regionu ze zmniejszoną ilością kolagenu podporowego⁵⁶⁵⁷.

Tworzenie się puli lipidów jest związane z infiltracją i odkładaniem się lipidów pochodzących z osocza⁵⁸. Wewnątrzpłytkowy krwotok odgrywa kluczową rolę w progresji i destabilizacji blaszek miażdżycowych, znacząco przyczyniając się do ekspansji jądra martwiczego, ponieważ czerwone krwinki są bogatym źródłem wolnego cholesterolu, który jest ważnym składnikiem pękniętych blaszek⁵⁹.

Zwapnienie blaszki miażdżycowej

Zwapnienie blaszki miażdżycowej jest kolejną cechą zaawansowanej miażdżycy. Istnieje jako formacja podobna do kości w obrębie blaszki i jest inicjowana w regionach zapalnych z lokalnym zmniejszeniem włókien kolagenowych⁶⁰⁶¹.

Badania wykazały, że pewne warunki mogą wpływać na stabilność blaszki i gojenie. Na przykład, cukrzyca jest związana z wyższą częstością występowania HPR i zwiększonym zwapnieniem tętnic, co wskazuje na bardziej aktywny proces aterogenny⁶².

Znaczenie czynników lipidowych w patogenezie miażdżycy

Gromadzące się dowody sugerują przyczynowy związek między cholesterolem we krwi a miażdżycą⁶³. LDL może być modyfikowane przez utlenianie in vivo i in vitro i jest wykrywalne zarówno w krążeniu, jak i w zmianach miażdżycowych⁶⁴.

Zgodnie z koncepcją odpowiedzi na zatrzymanie, kluczowym wydarzeniem inicjującym aterogenezę jest zatrzymanie tych bogatych w cholesterol lipoprotein zawierających apoB w ścianie tętnic, szczególnie w obecności dysfunkcji śródbłonka⁶⁵.

Po zatrzymaniu w ścianie tętnic, lipoproteiny ulegają modyfikacjom i ostatecznie wyzwalają szereg nieprawidłowych odpowiedzi, które przyspieszają dalsze zatrzymywanie lipoprotein i powodują dalszą progresję blaszki⁶⁶.

Oprócz ułatwienia wychwytu przez makrofagi i ostatecznie tworzenia komórek piankowatych, utlenione cząsteczki LDL promują miażdżycę poprzez dysfunkcję śródbłonka, rekrutację makrofagów, zwiększoną agregację płytek krwi i uwalnianie tromboksanu oraz zwiększoną apoptozę komórek mięśni gładkich i komórek śródbłonka⁶⁷.

Proaterogenne czynniki i enzymy, które są uwalniane przez monocyty/makrofagi w rozwijającym się atheroma, indukują tworzenie proteoglikanów o dużym powinowactwie do aterogennych lipoprotein, promując błędne koło, które prowadzi do dalszego zatrzymywania lipoprotein i progresji miażdżycy⁶⁸.

W patogenezie miażdżycy, lipoproteiny bogate w triglicerydy nasilają dysfunkcję śródbłonka, ułatwiają infiltrację monocytów do ściany tętnic i zwiększają aktywację genów prozapalnych⁶⁹.

Wpływ hiperlipidemii na rozwój miażdżycy

Hipercholesterolemia zwiększa powstawanie licznych biocząsteczek aterogennych, w tym reaktywnych form tlenu (ROS), cytokin prozapalnych [interleukina (IL)-1, IL-2, IL-6, IL-8, czynnik martwicy nowotworów alfa (TNF-α)], ekspresję cząsteczek adhezji międzykomórkowej-1 (ICAM-1), cząsteczek adhezji komórek naczyniowych-1 (VCAM-1), E-selektyny, białka chemotaktycznego monocytów-1 (MCP-1), czynnika stymulującego kolonie granulocytów i makrofagów (GM-CSF) oraz licznych czynników wzrostu [insulinopodobny czynnik wzrostu-1 (IGF-1), płytkopochodny czynnik wzrostu-1 (PDGF-1) i transformujący czynnik wzrostu beta (TGF-β)]⁷⁰.

ROS delikatnie utlenia cholesterol lipoprotein o niskiej gęstości (LDL-C) tworząc minimalnie zmodyfikowane LDL (MM-LDL), które jest dalej utleniane do utlenionego LDL (OX-LDL)⁷¹. Hipercholesterolemia aktywuje również czynnik jądrowy kappa-B (NF-κB)⁷².

Proponowany mechanizm miażdżycy wywołanej przez hipercholesterolemię opiera się na hipotezie oksydacyjnej miażdżycy, która została powszechnie zaakceptowana. Hipercholesterolemia zwiększa produkcję ROS i cytokin, które zwiększają ekspresję CAM w komórkach śródbłonka. Wczesnym krokiem w rozwoju miażdżycy jest przyleganie monocytów do komórek śródbłonka, co osiąga się za pomocą CAM. CAM uczestniczy w toczeniu i adhezji monocytów do komórek śródbłonka. Następnie monocyty przedostają się do przestrzeni podśródbłonkowej⁷³.

Hipercholesterolemia zwiększa również poziom AGE i AGE/sRAGE w surowicy oraz obniża poziom sRAGE w surowicy. Wzrost AGE i AGE/sRAGE oraz spadek sRAGE w surowicy zostały związane z rozwojem miażdżycy. Hipercholesterolemia zwiększa także poziom białka C-reaktywnego (CRP) w surowicy u ludzi. Wzrost białka C-reaktywnego zwiększa poziom aterogennych biocząsteczek w surowicy i indukuje rozwój miażdżycy⁷⁴.

Rola poszczególnych elementów komórkowych w patogenezie miażdżycy

Miażdżyca to choroba, która charakteryzuje się akumulacją komórek zapalnych, lipidów i tkanki łącznej w błonie wewnętrznej dużych i średnich tętnic, tworząc blaszki włóknisto-zapalne zwane ateromami⁷⁵.

Rola komórek śródbłonka (endotelium)

Śródbłonek naczyniowy odgrywa rolę regulacyjną w skurczu naczyń, relaksacji, proliferacji mięśni gładkich oraz ekspresji cząsteczek adhezyjnych lub czynników chemotaktycznych⁷⁶. Dysfunkcja śródbłonka występuje pod wpływem wielu czynników, w tym lokalnych zmian hemodynamicznych⁷⁷.

Stymulacja śródbłonka, znana również jako aktywacja śródbłonka typu I, występuje, gdy czynniki zapalne indukują odpowiedź, taką jak zmiana tonu mikronaczyniowego, przepuszczalności lub diapedezy leukocytów⁷⁸. Aktywowane komórki śródbłonka indukują selektywną rekrutację monocytów do błony wewnętrznej⁷⁹.

Rola makrofagów

Makrofagi odgrywają centralną rolę w patogenezie miażdżycy. Monocyty w podśródbłonku przekształcają się w makrofagi⁸⁰. Wychwyt utlenionych lipidów i przekształcenie makrofagów w komórki piankowate bogate w lipidy prowadzi do typowych wczesnych zmian miażdżycowych zwanych pasemkami tłuszczowymi⁸¹.

Makrofagi produkują prozapalne cytokiny, które rekrutują migrację komórek mięśni gładkich z błony środkowej oraz dalej przyciągają i stymulują wzrost makrofagów⁸². Zapalenia makrofagi uwalniają chemokiny/cytokiny, które promują zapalenie blaszki⁸³.

Rola komórek mięśni gładkich

Komórki mięśni gładkich naczyń (VSMCs) odgrywają kluczową rolę w formowaniu blaszki miażdżycowej. Kaskada dysfunkcji śródbłonkowej, akumulacji lipoprotein i szlaków zapalnych powoduje dramatyczne zmiany w fizjologii VSMCs⁸⁴.

W odpowiedzi na progresję zmiany miażdżycowej, więcej VSMCs jest rekrutowanych z tunica media do błony wewnętrznej, aby utworzyć czapeczkę włóknistą – warstwę ochronną, która pokrywa rdzeń martwicy⁸⁵.

Grubość czapeczki włóknistej pokrywającej miękki nekrotyczny rdzeń zmiany miażdżycowej, a także jej skład (ilość włókien kolagenowych/elastynowych), wpływają na stabilność blaszki i wyniki kliniczne⁸⁶.

Blaszki miażdżycowe mogą stać się bardziej podatne na uszkodzenia, jeśli VSMCs w czapeczce włóknistej odpowiadają na zapalenie, produkując enzymy, które degradują składniki macierzy zewnątrzkomórkowej, osłabiając czapeczkę włóknistą i czyniąc ją bardziej podatną na pęknięcie⁸⁷.

Integracja mechanizmów patogenetycznych miażdżycy

Miażdżyca to przewlekła choroba zapalna ściany tętnic powodowana przez czynniki ryzyka konwencjonalne i niekonwencjonalne, które prowadzą do rozwoju blaszek w błonie wewnętrznej naczyń⁸⁸.

Zapalenie śródbłonka naczyniowego, napędzane przez komórki odpornościowe, takie jak makrofagi, przyspiesza niestabilność blaszki miażdżycowej poprzez promowanie rozpadu kolagenu i ścieńczanie czapeczki włóknistej, co zwiększa prawdopodobieństwo pęknięcia i zakrzepicy⁸⁹.

Głównym udokumentowanym czynnikiem napędzającym ten proces są utlenione cząsteczki lipoprotein w ścianie, pod komórkami śródbłonka, chociaż górne normalne lub podwyższone stężenia glukozy we krwi również odgrywają główną rolę, a nie wszystkie czynniki są w pełni zrozumiałe⁹⁰.

Nieustające procesy zapalne akumulacji lipoprotein, tworzenia komórek piankowatych i aktywacji immunologicznej prowadzą do włóknisto-komórkowej organizacji blaszki, przy czym blaszka staje się coraz bardziej niestabilna i podatna na pęknięcie i ostrą zakrzepicę poprzez ścieńczanie czapeczki włóknistej i ekspansję nekrotycznego jądra lipidowego⁹¹.

Miażdżyca rozwija się jako przewlekła odpowiedź zapalna ściany tętniczej na uraz śródbłonka. Progresja zmiany następuje poprzez interakcje zmodyfikowanych lipoprotein, makrofagów pochodzących z monocytów, limfocytów T i normalnych składników komórkowych ściany tętnic⁹².

Rozwój miażdżycy to stopniowy proces trwający kilkadziesiąt lat jako odpowiedź na uszkodzenie ściany tętniczej przez czynniki ryzyka, takie jak hipercholesterolemia i nadciśnienie. Złożone blaszki mogą pęknąć, powodując zakrzepicę, zatorowość i niedrożność naczyń, prowadząc do powikłań, takich jak zawał mięśnia sercowego⁹³.

Kolejne rozdziały

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Materiały źródłowe

#1 Arteriosclerosis | Radiology Reference Article | Radiopaedia.org
https://radiopaedia.org/articles/arteriosclerosis?lang=us
Arteriosclerosis is defined by thickening and loss of elasticity of the arterial walls. […] Atherosclerosis is characterized by atheromatous plaques in the intima of large and medium-sized arteries. It is the most common form of arteriosclerosis. […] Atheromatous plaques begin as fatty streaks composed of lipid-laden macrophages (foam cells). This process begins in childhood but not all fatty streaks progress to plaques. […] The underlying pathogenesis is not completely understood but is believed to involve chronic endothelial injury which results in an inflammatory response, accumulation of lipids, platelet aggregation and activation of smooth muscle cells. […] Plaques form most commonly in large elastic arteries (e.g. aorta, carotids, iliacs), and large and medium-sized muscular arteries (e.g. coronary, renal, lower limb, mesenteric and cerebral vessels). They are most prominent at branching points and ostia of major branches.
#2 Arteriosclerosis / atherosclerosis – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/arteriosclerosis-atherosclerosis/symptoms-causes/syc-20350569
Arteriosclerosis and atherosclerosis are sometimes used to mean the same thing. But there’s a difference between the two terms. […] Arteriosclerosis happens when the blood vessels that carry oxygen and nutrients from the heart to the rest of the body become thick and stiff. These blood vessels are called arteries. Healthy arteries are flexible and elastic. But over time, the walls in the arteries can harden, a condition commonly called hardening of the arteries. […] Atherosclerosis is a specific type of arteriosclerosis. […] Atherosclerosis is the buildup of fats, cholesterol and other substances in and on the artery walls. This buildup is called plaque. The plaque can cause arteries to narrow, blocking blood flow. The plaque also can burst, leading to a blood clot. […] Atherosclerosis is a disease that slowly gets worse. It may begin as early as childhood. The exact cause is not known. It may start with damage or injury to the inner layer of an artery. Artery damage may be caused by: High blood pressure. High cholesterol. High triglycerides, a type of fat in the blood. Smoking or other tobacco use. Diabetes. Insulin resistance. Obesity. Inflammation from an unknown cause or from diseases such as arthritis, lupus, psoriasis or inflammatory bowel disease.
#3 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Atherosclerosis is the main risk factor for cardiovascular disease (CVD), which is the leading cause of mortality worldwide. Atherosclerosis is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. The resultant atheroma plaque, along with these processes, results in cardiovascular complications. […] Atherosclerosis initiates upon endothelial dysfunction accompanied by low-density lipoprotein (LDL) retention and its modification in the intima. Modified LDLs, together with additional atherogenic factors, promote the activation of ECs, leading to monocyte recruitment within the intima. Modified LDLs are avidly captured by differentiated monocytes and VSMC, which promote foam cell formation.
#4 Pathophysiology of Atherosclerosis
https://www.mdpi.com/1422-0067/23/6/3346
Atherosclerosis is the main risk factor for cardiovascular disease (CVD), which is the leading cause of mortality worldwide. Atherosclerosis is initiated by endothelium activation and, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification), triggers the vessel narrowing and activation of inflammatory pathways. The resultant atheroma plaque, along with these processes, results in cardiovascular complications. […] Atherosclerosis initiates upon endothelial dysfunction accompanied by low-density lipoprotein (LDL) retention and its modification in the intima. Modified LDLs, together with additional atherogenic factors, promote the activation of ECs, leading to monocyte recruitment within the intima. Modified LDLs are avidly captured by differentiated monocytes and VSMC, which promote foam cell formation.
#5 Atherosclerosis – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534258/
Atherosclerosis, the principal cause of heart attack, stroke, and peripheral vascular disease, remains a major contributor to morbidity and mortality in the Western World. […] Although the aetiology of atherosclerosis is not fully understood, it is generally accepted that atherosclerosis is a multifactorial disease induced by the effects of various risk factors on appropriate genetic backgrounds. […] Many risk factors, such as hypercholesterolemia, modified lipoproteins, hypertension, diabetes, infections and smoking have been identified in the development of atherosclerosis. […] Although formerly considered a bland lipid storage disease, new insights into the pathogenesis of atherosclerosis have emerged during the last decades, due to the progress of cellular and molecular approaches to the study of cell interactions in the arterial wall as well as alterations of lipid metabolism.
#6 Atherosclerosis – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534258/
The response to injury hypothesis relies on the concept that the primary cause of atherosclerosis is an injury to the arterial endothelium induced by various factors, i.e. smoking, mechanical stress, oxidized-LDL, homocysteine, immunological events, toxins, viruses, etc. […] The oxidized LDL hypothesis postulates that LDL oxidized by various factors including endothelial cells, macrophages and smooth muscle cells of the arterial wall, plays a key role in the development of atherosclerosis. […] More recently, a widely accepted hypothesis is that atherosclerosis is an inflammatory disease, because recent advances in the basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis.
#7 Atherosclerosis – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534258/
The response to injury hypothesis relies on the concept that the primary cause of atherosclerosis is an injury to the arterial endothelium induced by various factors, i.e. smoking, mechanical stress, oxidized-LDL, homocysteine, immunological events, toxins, viruses, etc. […] The oxidized LDL hypothesis postulates that LDL oxidized by various factors including endothelial cells, macrophages and smooth muscle cells of the arterial wall, plays a key role in the development of atherosclerosis. […] More recently, a widely accepted hypothesis is that atherosclerosis is an inflammatory disease, because recent advances in the basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis.
#8 Atherosclerosis – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534258/
The response to injury hypothesis relies on the concept that the primary cause of atherosclerosis is an injury to the arterial endothelium induced by various factors, i.e. smoking, mechanical stress, oxidized-LDL, homocysteine, immunological events, toxins, viruses, etc. […] The oxidized LDL hypothesis postulates that LDL oxidized by various factors including endothelial cells, macrophages and smooth muscle cells of the arterial wall, plays a key role in the development of atherosclerosis. […] More recently, a widely accepted hypothesis is that atherosclerosis is an inflammatory disease, because recent advances in the basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis.
#9 Atherosclerosis | Nature Reviews Disease Primers
https://www.nature.com/articles/s41572-019-0106-z
Atherosclerosis, the formation of fibrofatty lesions in the artery wall, causes much morbidity and mortality worldwide, including most myocardial infarctions and many strokes, as well as disabling peripheral artery disease. […] Development of atherosclerotic lesions probably requires low-density lipoprotein, a particle that carries cholesterol through the blood. […] Other risk factors for atherosclerosis and its thrombotic complications include hypertension, cigarette smoking and diabetes mellitus. […] Increasing evidence also points to a role of the immune system, as emerging risk factors include inflammation and clonal haematopoiesis. […] Studies of the cell and molecular biology of atherogenesis have provided considerable insight into the mechanisms that link all these risk factors to atheroma development and the clinical manifestations of this disease.
#10 What is the role of lipids in atherosclerosis and how low should we decrease lipid levels?
https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/what-is-the-role-of-lipids-in-atherosclerosis-and-how-low-should-we-decrease-lip
Retention of apolipoprotein-B-containing lipoproteins within the arterial wall is the key initiating event in the pathobiology of atherosclerosis. […] Compelling evidence from preclinical investigations, Mendelian randomisation studies, epidemiologic observations, and randomised trials of lipid-modifying medications supports the key causal role of atherogenic lipoproteins, particularly low-density lipoprotein (LDL), in the pathogenesis of ASCVD. […] Importantly, dyslipidaemia is a modifiable risk factor, and pharmacologic LDL-cholesterol (LDL-C) lowering has been shown to halt the progression of atherosclerosis and improve clinical outcomes in the context of primary as well as secondary prevention. […] The totality of currently available evidence indicates that the greater the absolute reduction in plasma LDL-C levels, the larger the reduction of ASCVD risk, without offsetting safety issues arising from intensive lipid-lowering strategies.
#11 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Disruption of the mechanisms involved in vascular homeostasis regulation leads to endothelial dysfunction. Briefly, when ECs lose their ability to maintain homeostasis, vessel walls are predisposed to vasoconstriction, lipid infiltration, leukocyte adhesion, platelet activation, and oxidative stress, among other things. Together, these induce an inflammatory response that is considered the first step of atheromatous plaque formation: the fatty streak. […] Hemodynamic forces constitute a local risk factor of atherogenesis, as they promote endothelial dysfunction. […] Endothelial dysfunction is also explained through a reduction in NO bioavailability. NO is synthesized from L-arginine in ECs in a reaction catalyzed by eNOS and diffuses across cell membranes, reaching the smooth muscle tissue of the artery wall. NO promotes smooth muscle fiber relaxation, known as endothelium-dependent vasodilatation, and is considered an athero-protective molecule, because it counteracts atherogenesis and its complications.
#12 Pathophysiology of Atherosclerosis
https://www.mdpi.com/1422-0067/23/6/3346
Disruption of the mechanisms involved in vascular homeostasis regulation leads to endothelial dysfunction. Briefly, when ECs lose their ability to maintain homeostasis, vessel walls are predisposed to vasoconstriction, lipid infiltration, leukocyte adhesion, platelet activation, and oxidative stress, among other things. Together, these induce an inflammatory response that is considered the first step of atheromatous plaque formation: the fatty streak. […] Hemodynamic forces constitute a local risk factor of atherogenesis, as they promote endothelial dysfunction. […] Endothelial dysfunction is also explained through a reduction in NO bioavailability. NO is synthesized from L-arginine in ECs in a reaction catalyzed by eNOS and diffuses across cell membranes, reaching the smooth muscle tissue of the artery wall. NO promotes smooth muscle fiber relaxation, known as endothelium-dependent vasodilatation, and is considered an athero-protective molecule, because it counteracts atherogenesis and its complications.
#13 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Disruption of the mechanisms involved in vascular homeostasis regulation leads to endothelial dysfunction. Briefly, when ECs lose their ability to maintain homeostasis, vessel walls are predisposed to vasoconstriction, lipid infiltration, leukocyte adhesion, platelet activation, and oxidative stress, among other things. Together, these induce an inflammatory response that is considered the first step of atheromatous plaque formation: the fatty streak. […] Hemodynamic forces constitute a local risk factor of atherogenesis, as they promote endothelial dysfunction. […] Endothelial dysfunction is also explained through a reduction in NO bioavailability. NO is synthesized from L-arginine in ECs in a reaction catalyzed by eNOS and diffuses across cell membranes, reaching the smooth muscle tissue of the artery wall. NO promotes smooth muscle fiber relaxation, known as endothelium-dependent vasodilatation, and is considered an athero-protective molecule, because it counteracts atherogenesis and its complications.
#14 Pathophysiology of Atherosclerosis
https://www.mdpi.com/1422-0067/23/6/3346
Disruption of the mechanisms involved in vascular homeostasis regulation leads to endothelial dysfunction. Briefly, when ECs lose their ability to maintain homeostasis, vessel walls are predisposed to vasoconstriction, lipid infiltration, leukocyte adhesion, platelet activation, and oxidative stress, among other things. Together, these induce an inflammatory response that is considered the first step of atheromatous plaque formation: the fatty streak. […] Hemodynamic forces constitute a local risk factor of atherogenesis, as they promote endothelial dysfunction. […] Endothelial dysfunction is also explained through a reduction in NO bioavailability. NO is synthesized from L-arginine in ECs in a reaction catalyzed by eNOS and diffuses across cell membranes, reaching the smooth muscle tissue of the artery wall. NO promotes smooth muscle fiber relaxation, known as endothelium-dependent vasodilatation, and is considered an athero-protective molecule, because it counteracts atherogenesis and its complications.
#15 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Nonlaminar or turbulent blood flow (eg, at branch points in the arterial tree) leads to endothelial dysfunction and inhibits endothelial production of nitric oxide, a potent vasodilator and anti-inflammatory molecule. Such blood flow also stimulates endothelial cells to produce adhesion molecules, which recruit and bind inflammatory cells. […] Risk factors for atherosclerosis (eg, dyslipidemia, diabetes, cigarette smoking, hypertension), oxidative stressors (eg, superoxide radicals), angiotensin II, and systemic infection and inflammation also inhibit nitric oxide production and stimulate production of adhesion molecules, proinflammatory cytokines, chemotactic proteins, and vasoconstrictors; exact mechanisms are unknown. […] The net effect is endothelial binding of monocytes and T cells, migration of these cells to the subendothelial space, and initiation and perpetuation of a local vascular inflammatory response.
#16 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Disruption of the mechanisms involved in vascular homeostasis regulation leads to endothelial dysfunction. Briefly, when ECs lose their ability to maintain homeostasis, vessel walls are predisposed to vasoconstriction, lipid infiltration, leukocyte adhesion, platelet activation, and oxidative stress, among other things. Together, these induce an inflammatory response that is considered the first step of atheromatous plaque formation: the fatty streak. […] Hemodynamic forces constitute a local risk factor of atherogenesis, as they promote endothelial dysfunction. […] Endothelial dysfunction is also explained through a reduction in NO bioavailability. NO is synthesized from L-arginine in ECs in a reaction catalyzed by eNOS and diffuses across cell membranes, reaching the smooth muscle tissue of the artery wall. NO promotes smooth muscle fiber relaxation, known as endothelium-dependent vasodilatation, and is considered an athero-protective molecule, because it counteracts atherogenesis and its complications.
#17 Pathophysiology of Atherosclerosis
https://www.mdpi.com/1422-0067/23/6/3346
Disruption of the mechanisms involved in vascular homeostasis regulation leads to endothelial dysfunction. Briefly, when ECs lose their ability to maintain homeostasis, vessel walls are predisposed to vasoconstriction, lipid infiltration, leukocyte adhesion, platelet activation, and oxidative stress, among other things. Together, these induce an inflammatory response that is considered the first step of atheromatous plaque formation: the fatty streak. […] Hemodynamic forces constitute a local risk factor of atherogenesis, as they promote endothelial dysfunction. […] Endothelial dysfunction is also explained through a reduction in NO bioavailability. NO is synthesized from L-arginine in ECs in a reaction catalyzed by eNOS and diffuses across cell membranes, reaching the smooth muscle tissue of the artery wall. NO promotes smooth muscle fiber relaxation, known as endothelium-dependent vasodilatation, and is considered an athero-protective molecule, because it counteracts atherogenesis and its complications.
#18 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Accumulation of LDL in plasma favors transendothelial infiltration of circulating LDLs to the intima. […] Once in the subendothelial space, trapped LDL particles are oxidized, a process facilitated by the absence of protective plasma antioxidants, such as tocopherol, ascorbate, urate, apolipoproteins, or serum albumin. Oxidized LDLs are key inflammatory components that promote atherosclerotic plaque development, as they contain oxidized lipids and products derived from their degradation that contribute to the physiopathology of the disease. […] Endothelial stimulation, also known as endothelial type I activation, occurs when inflammatory agents induce a response such as a change in microvascular tone, permeability, or leukocyte diapedesis. […] Activated ECs induce selective monocyte recruitment into the intima.
#19 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Accumulation of LDL in plasma favors transendothelial infiltration of circulating LDLs to the intima. […] Once in the subendothelial space, trapped LDL particles are oxidized, a process facilitated by the absence of protective plasma antioxidants, such as tocopherol, ascorbate, urate, apolipoproteins, or serum albumin. Oxidized LDLs are key inflammatory components that promote atherosclerotic plaque development, as they contain oxidized lipids and products derived from their degradation that contribute to the physiopathology of the disease. […] Endothelial stimulation, also known as endothelial type I activation, occurs when inflammatory agents induce a response such as a change in microvascular tone, permeability, or leukocyte diapedesis. […] Activated ECs induce selective monocyte recruitment into the intima.
#20 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Accumulation of LDL in plasma favors transendothelial infiltration of circulating LDLs to the intima. […] Once in the subendothelial space, trapped LDL particles are oxidized, a process facilitated by the absence of protective plasma antioxidants, such as tocopherol, ascorbate, urate, apolipoproteins, or serum albumin. Oxidized LDLs are key inflammatory components that promote atherosclerotic plaque development, as they contain oxidized lipids and products derived from their degradation that contribute to the physiopathology of the disease. […] Endothelial stimulation, also known as endothelial type I activation, occurs when inflammatory agents induce a response such as a change in microvascular tone, permeability, or leukocyte diapedesis. […] Activated ECs induce selective monocyte recruitment into the intima.
#21 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Accumulation of LDL in plasma favors transendothelial infiltration of circulating LDLs to the intima. […] Once in the subendothelial space, trapped LDL particles are oxidized, a process facilitated by the absence of protective plasma antioxidants, such as tocopherol, ascorbate, urate, apolipoproteins, or serum albumin. Oxidized LDLs are key inflammatory components that promote atherosclerotic plaque development, as they contain oxidized lipids and products derived from their degradation that contribute to the physiopathology of the disease. […] Endothelial stimulation, also known as endothelial type I activation, occurs when inflammatory agents induce a response such as a change in microvascular tone, permeability, or leukocyte diapedesis. […] Activated ECs induce selective monocyte recruitment into the intima.
#22 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. […] Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. […] Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. […] The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. […] A process similar to bone formation causes calcification within the plaque.
#23 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. […] Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. […] Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. […] The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. […] A process similar to bone formation causes calcification within the plaque.
#24 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. […] Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. […] Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. […] The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. […] A process similar to bone formation causes calcification within the plaque.
#25 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. […] Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. […] Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. […] The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. […] A process similar to bone formation causes calcification within the plaque.
#26 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. […] Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. […] Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. […] The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. […] A process similar to bone formation causes calcification within the plaque.
#27 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Atherosclerotic plaques may be stable or unstable. […] Stable plaques regress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion. […] Unstable plaques are vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. […] The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. […] Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. […] These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. […] Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque.
#28 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Atherosclerotic plaques may be stable or unstable. […] Stable plaques regress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion. […] Unstable plaques are vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. […] The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. […] Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. […] These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. […] Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque.
#29 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Atherosclerotic plaques may be stable or unstable. […] Stable plaques regress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion. […] Unstable plaques are vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. […] The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. […] Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. […] These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. […] Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque.
#30 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Atherosclerotic plaques may be stable or unstable. […] Stable plaques regress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion. […] Unstable plaques are vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. […] The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. […] Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. […] These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. […] Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque.
#31 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Atherosclerotic plaques may be stable or unstable. […] Stable plaques regress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion. […] Unstable plaques are vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. […] The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. […] Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. […] These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. […] Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque.
#32 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Atherosclerotic plaques may be stable or unstable. […] Stable plaques regress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion. […] Unstable plaques are vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. […] The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. […] Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. […] These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. […] Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque.
#33 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Atherosclerotic plaques may be stable or unstable. […] Stable plaques regress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion. […] Unstable plaques are vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. […] The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. […] Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. […] These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. […] Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque.
#34 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Once the plaque ruptures, plaque contents are exposed to circulating blood, triggering thrombosis; macrophages also stimulate thrombosis because they contain tissue factor, which promotes thrombin generation in vivo. […] Atherosclerosis is initially asymptomatic, often for decades. Symptoms and signs develop when lesions impede blood flow. […] Atherosclerosis may also cause sudden death without preceding stable or unstable angina pectoris.
#35 Pathophysiology of Atherosclerosis
https://www.mdpi.com/1422-0067/23/6/3346
Atheroma plaque calcification is another hallmark of advanced atherosclerosis. It exists as a bone-like formation within the plaque and is initiated in inflammatory regions with a local decrease in collagen fibers. […] A plaque is considered vulnerable when the lesion shows a large necrotic core, a thin fibrous cap, and an increased inflammatory response due to the continuous exposure to the pro-atherogenic milieu. […] When the plaque fissures or ruptures, the subendothelial space is exposed to blood, triggering a coagulation process to cover the wound.
#36 Pathophysiology of Atherosclerosis
https://www.mdpi.com/1422-0067/23/6/3346
Atheroma plaque calcification is another hallmark of advanced atherosclerosis. It exists as a bone-like formation within the plaque and is initiated in inflammatory regions with a local decrease in collagen fibers. […] A plaque is considered vulnerable when the lesion shows a large necrotic core, a thin fibrous cap, and an increased inflammatory response due to the continuous exposure to the pro-atherogenic milieu. […] When the plaque fissures or ruptures, the subendothelial space is exposed to blood, triggering a coagulation process to cover the wound.
#37 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
Atherosclerosis imposes a heavy burden on cardiovascular health due to its indispensable role in the pathogenesis of cardiovascular disease (CVD) such as coronary artery disease and heart failure. […] Ample clinical and experimental evidence has corroborated the vital role of inflammation in the pathophysiology of atherosclerosis. […] The pathophysiology of atherosclerosis is closely linked with inflammation and its transition to chronic inflammation. […] Monocytes/macrophages are at the center of driving plaque inflammation in atherosclerosis with broad and complicated molecular mechanisms, which are not fully deciphered. […] The excessive retention or oxidation of LDL in the arterial subendothelial layer provokes monocyte generation from progenitor cells in the BM and their subsequent release into the circulation.
#38 Novel Insights into the Molecular Mechanisms of Atherosclerosis
https://www.mdpi.com/1422-0067/24/17/13434
Atherosclerosis is one of the most fatal diseases in the world. The associated thickening of the arterial wall and its background and consequences make it a very composite disease entity with many mechanisms that lead to its creation. […] The identification of atherogenesis as an active process rather than a passive cholesterol storage disease has highlighted important inflammatory, molecular, and cellular pathways. […] Inflammation starts with inflammasomes, which are innate immunological signaling complexes that are a significant modulator of IL-1 family cytokine production in atherosclerosis, contributing to the vascular inflammatory response that drives the development and progression of atherosclerosis. […] The pathogeneses of atherosclerosis and diabetes are closely related. Diabetes has been shown to be a triggering factor for atherosclerosis due to dyslipidemia, hyperglycemia, oxidative stress, and chronic inflammation.
#39 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
Atherosclerosis imposes a heavy burden on cardiovascular health due to its indispensable role in the pathogenesis of cardiovascular disease (CVD) such as coronary artery disease and heart failure. […] Ample clinical and experimental evidence has corroborated the vital role of inflammation in the pathophysiology of atherosclerosis. […] The pathophysiology of atherosclerosis is closely linked with inflammation and its transition to chronic inflammation. […] Monocytes/macrophages are at the center of driving plaque inflammation in atherosclerosis with broad and complicated molecular mechanisms, which are not fully deciphered. […] The excessive retention or oxidation of LDL in the arterial subendothelial layer provokes monocyte generation from progenitor cells in the BM and their subsequent release into the circulation.
#40 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
Atherosclerosis imposes a heavy burden on cardiovascular health due to its indispensable role in the pathogenesis of cardiovascular disease (CVD) such as coronary artery disease and heart failure. […] Ample clinical and experimental evidence has corroborated the vital role of inflammation in the pathophysiology of atherosclerosis. […] The pathophysiology of atherosclerosis is closely linked with inflammation and its transition to chronic inflammation. […] Monocytes/macrophages are at the center of driving plaque inflammation in atherosclerosis with broad and complicated molecular mechanisms, which are not fully deciphered. […] The excessive retention or oxidation of LDL in the arterial subendothelial layer provokes monocyte generation from progenitor cells in the BM and their subsequent release into the circulation.
#41 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
Atherosclerosis imposes a heavy burden on cardiovascular health due to its indispensable role in the pathogenesis of cardiovascular disease (CVD) such as coronary artery disease and heart failure. […] Ample clinical and experimental evidence has corroborated the vital role of inflammation in the pathophysiology of atherosclerosis. […] The pathophysiology of atherosclerosis is closely linked with inflammation and its transition to chronic inflammation. […] Monocytes/macrophages are at the center of driving plaque inflammation in atherosclerosis with broad and complicated molecular mechanisms, which are not fully deciphered. […] The excessive retention or oxidation of LDL in the arterial subendothelial layer provokes monocyte generation from progenitor cells in the BM and their subsequent release into the circulation.
#42 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
Inflammatory macrophages release chemokines/cytokines, which promote plaque inflammation. […] As the plaque grows, it becomes unstable and may rupture. […] Due to the inflammatory milieu of the plaque, procoagulant factors are activated and fibrin production increases. […] While efferocytosis prevents inflammation and plaque growth, the impaired efferocytosis of apoptotic/necrotic bodies may lead to further deposition of macrophages/foam cells in the plaque. […] The oxidation of LDL promotes its uptake by macrophages in the intimal layer. […] Hence, beyond the primary events, inflammation plays a decisive role in the exacerbation of the plaque and the progression of atherosclerosis. […] Stable plaques are featured by chronic low-grade inflammation, while unstable plaques exhibit active inflammation, which further promotes plaque rupture and vulnerability by thinning the fibrous cap.
#43 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
Inflammatory macrophages release chemokines/cytokines, which promote plaque inflammation. […] As the plaque grows, it becomes unstable and may rupture. […] Due to the inflammatory milieu of the plaque, procoagulant factors are activated and fibrin production increases. […] While efferocytosis prevents inflammation and plaque growth, the impaired efferocytosis of apoptotic/necrotic bodies may lead to further deposition of macrophages/foam cells in the plaque. […] The oxidation of LDL promotes its uptake by macrophages in the intimal layer. […] Hence, beyond the primary events, inflammation plays a decisive role in the exacerbation of the plaque and the progression of atherosclerosis. […] Stable plaques are featured by chronic low-grade inflammation, while unstable plaques exhibit active inflammation, which further promotes plaque rupture and vulnerability by thinning the fibrous cap.
#44 Novel Insights into the Molecular Mechanisms of Atherosclerosis
https://www.mdpi.com/1422-0067/24/17/13434
Atherosclerosis is one of the most fatal diseases in the world. The associated thickening of the arterial wall and its background and consequences make it a very composite disease entity with many mechanisms that lead to its creation. […] The identification of atherogenesis as an active process rather than a passive cholesterol storage disease has highlighted important inflammatory, molecular, and cellular pathways. […] Inflammation starts with inflammasomes, which are innate immunological signaling complexes that are a significant modulator of IL-1 family cytokine production in atherosclerosis, contributing to the vascular inflammatory response that drives the development and progression of atherosclerosis. […] The pathogeneses of atherosclerosis and diabetes are closely related. Diabetes has been shown to be a triggering factor for atherosclerosis due to dyslipidemia, hyperglycemia, oxidative stress, and chronic inflammation.
#45 Novel Insights into the Molecular Mechanisms of Atherosclerosis
https://www.mdpi.com/1422-0067/24/17/13434
Atherosclerosis is one of the most fatal diseases in the world. The associated thickening of the arterial wall and its background and consequences make it a very composite disease entity with many mechanisms that lead to its creation. […] The identification of atherogenesis as an active process rather than a passive cholesterol storage disease has highlighted important inflammatory, molecular, and cellular pathways. […] Inflammation starts with inflammasomes, which are innate immunological signaling complexes that are a significant modulator of IL-1 family cytokine production in atherosclerosis, contributing to the vascular inflammatory response that drives the development and progression of atherosclerosis. […] The pathogeneses of atherosclerosis and diabetes are closely related. Diabetes has been shown to be a triggering factor for atherosclerosis due to dyslipidemia, hyperglycemia, oxidative stress, and chronic inflammation.
#46 Mechanism of Hypercholesterolemia-Induced Atherosclerosis
https://www.imrpress.com/journal/RCM/23/6/10.31083/j.rcm2306212/htm
Hypercholesterolemia generates ROS. The question arises if hypercholesterolemia-induced ROS induces atherosclerosis. This section describes the increases in the levels of ROS and the indirect measures of ROS in hypercholesterolemic atherosclerosis. Indirect measures of ROS include lipid peroxidation products, malondialdehyde (MDA), aortic tissue chemiluminescence (AO-CL), a polymorphonuclear leukocyte chemiluminescence (PMNL-CL) and white blood cell chemiluminescence (WBC-CL). AO-CL is a measure of antioxidant reserve. An increase in AO-CL suggests a decrease in the antioxidant reserve and vice-versa. […] Hypercholesterolemia increases the activity of the oxidant producing enzyme system, NADPH-oxidase, and xanthine oxidase. Hypercholesterolemia activates NF-ÎºB. Circulating NF-ÎºB is elevated in familial hypercholesterolemia. Hypercholesterolemia increases the soluble cell adhesion molecules (sICAM-1, sVCASM-1, sE-selectin). The serum levels of IL-6, IL-8, IL-12, TNF-Î± and IFN-Î³ increased, while that of IL-4 and IL-10 decreased in hypercholesterolemia. Hypercholesterolemia increases the levels of circulating MCP-1. The serum levels of GM-CSF are elevated in hypercholesterolemic patients. Plasma levels of PAF have been reported to rise in hypercholesterolemic patients. Plasma levels of LTB4, which promotes atherosclerosis, are elevated in hypercholesterolemic rats. Activated C3 is elevated in hypercholesterolemic apo-E-null mice and patients with familial hypercholesterolemia. In summary, the atherogenic biomolecules are elevated in hypercholesterolemic subjects.
#47 Pathophysiology of Atherosclerosis – Pathology
https://pressbooks.bccampus.ca/pathology/chapter/pathophysiology-of-atherosclerosis-and-angina/
Atherosclerosis plaque formation begins with activation and/or damage to the endothelium, which disrupts the normal process of LDL intake and metabolism. […] Oxidized LDL (oxLDL) is a key inflammatory component that facilitates atherosclerosis progression. […] These initial processes create a vicious circle that results in further recruitment of monocytes, LDL retention, and oxLDL accumulation. […] As the vicious circle progresses, LDL is deposited both inside cells and in the extracellular matrix, and cholesterol crystals form. […] Foam cells (derived from macrophages and VSMCs) undergo cellular death (apoptosis) and release their contents within the tunica intima. […] In response to the atherosclerotic lesion progression, more VSMCs are recruited from the tunica media to the intima to form a fibrous cap a protective layer that covers the necrotic core.
#48 Mechanism of Hypercholesterolemia-Induced Atherosclerosis
https://www.imrpress.com/journal/RCM/23/6/10.31083/j.rcm2306212/htm
Hypercholesterolemia generates ROS. The question arises if hypercholesterolemia-induced ROS induces atherosclerosis. This section describes the increases in the levels of ROS and the indirect measures of ROS in hypercholesterolemic atherosclerosis. Indirect measures of ROS include lipid peroxidation products, malondialdehyde (MDA), aortic tissue chemiluminescence (AO-CL), a polymorphonuclear leukocyte chemiluminescence (PMNL-CL) and white blood cell chemiluminescence (WBC-CL). AO-CL is a measure of antioxidant reserve. An increase in AO-CL suggests a decrease in the antioxidant reserve and vice-versa. […] Hypercholesterolemia increases the activity of the oxidant producing enzyme system, NADPH-oxidase, and xanthine oxidase. Hypercholesterolemia activates NF-ÎºB. Circulating NF-ÎºB is elevated in familial hypercholesterolemia. Hypercholesterolemia increases the soluble cell adhesion molecules (sICAM-1, sVCASM-1, sE-selectin). The serum levels of IL-6, IL-8, IL-12, TNF-Î± and IFN-Î³ increased, while that of IL-4 and IL-10 decreased in hypercholesterolemia. Hypercholesterolemia increases the levels of circulating MCP-1. The serum levels of GM-CSF are elevated in hypercholesterolemic patients. Plasma levels of PAF have been reported to rise in hypercholesterolemic patients. Plasma levels of LTB4, which promotes atherosclerosis, are elevated in hypercholesterolemic rats. Activated C3 is elevated in hypercholesterolemic apo-E-null mice and patients with familial hypercholesterolemia. In summary, the atherogenic biomolecules are elevated in hypercholesterolemic subjects.
#49 Mechanism of Hypercholesterolemia-Induced Atherosclerosis
https://www.imrpress.com/journal/RCM/23/6/10.31083/j.rcm2306212/htm
Hypercholesterolemia generates ROS. The question arises if hypercholesterolemia-induced ROS induces atherosclerosis. This section describes the increases in the levels of ROS and the indirect measures of ROS in hypercholesterolemic atherosclerosis. Indirect measures of ROS include lipid peroxidation products, malondialdehyde (MDA), aortic tissue chemiluminescence (AO-CL), a polymorphonuclear leukocyte chemiluminescence (PMNL-CL) and white blood cell chemiluminescence (WBC-CL). AO-CL is a measure of antioxidant reserve. An increase in AO-CL suggests a decrease in the antioxidant reserve and vice-versa. […] Hypercholesterolemia increases the activity of the oxidant producing enzyme system, NADPH-oxidase, and xanthine oxidase. Hypercholesterolemia activates NF-ÎºB. Circulating NF-ÎºB is elevated in familial hypercholesterolemia. Hypercholesterolemia increases the soluble cell adhesion molecules (sICAM-1, sVCASM-1, sE-selectin). The serum levels of IL-6, IL-8, IL-12, TNF-Î± and IFN-Î³ increased, while that of IL-4 and IL-10 decreased in hypercholesterolemia. Hypercholesterolemia increases the levels of circulating MCP-1. The serum levels of GM-CSF are elevated in hypercholesterolemic patients. Plasma levels of PAF have been reported to rise in hypercholesterolemic patients. Plasma levels of LTB4, which promotes atherosclerosis, are elevated in hypercholesterolemic rats. Activated C3 is elevated in hypercholesterolemic apo-E-null mice and patients with familial hypercholesterolemia. In summary, the atherogenic biomolecules are elevated in hypercholesterolemic subjects.
#50 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
Inflammatory macrophages release chemokines/cytokines, which promote plaque inflammation. […] As the plaque grows, it becomes unstable and may rupture. […] Due to the inflammatory milieu of the plaque, procoagulant factors are activated and fibrin production increases. […] While efferocytosis prevents inflammation and plaque growth, the impaired efferocytosis of apoptotic/necrotic bodies may lead to further deposition of macrophages/foam cells in the plaque. […] The oxidation of LDL promotes its uptake by macrophages in the intimal layer. […] Hence, beyond the primary events, inflammation plays a decisive role in the exacerbation of the plaque and the progression of atherosclerosis. […] Stable plaques are featured by chronic low-grade inflammation, while unstable plaques exhibit active inflammation, which further promotes plaque rupture and vulnerability by thinning the fibrous cap.
#51 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
These findings corroborate the indispensable role of inflammation in the progression of atherosclerosis. […] The hypoxia-induced activation of HIF-1 in macrophages may lead to the downregulation of PPAR-, thus driving plaque inflammation by reactivating proinflammatory genes and the repression of anti-inflammatory genes. […] Overall, these findings would suggest that hypoxia activates mTORC1 in macrophages, leading to plaque inflammation via NF-B and HIF-1 signalings. […] The binding and uptake of oxLDL by CD36 induce the activation of vimentin/FAK/NF-B axis in macrophages, resulting in cytokine release and inflammation. […] In summary, the described studies have shed light on the potential underlying mechanisms of macrophage-mediated inflammation after the exposure or uptake of oxLDL in atherosclerotic plaques.
#52 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
These findings corroborate the indispensable role of inflammation in the progression of atherosclerosis. […] The hypoxia-induced activation of HIF-1 in macrophages may lead to the downregulation of PPAR-, thus driving plaque inflammation by reactivating proinflammatory genes and the repression of anti-inflammatory genes. […] Overall, these findings would suggest that hypoxia activates mTORC1 in macrophages, leading to plaque inflammation via NF-B and HIF-1 signalings. […] The binding and uptake of oxLDL by CD36 induce the activation of vimentin/FAK/NF-B axis in macrophages, resulting in cytokine release and inflammation. […] In summary, the described studies have shed light on the potential underlying mechanisms of macrophage-mediated inflammation after the exposure or uptake of oxLDL in atherosclerotic plaques.
#53 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
These findings corroborate the indispensable role of inflammation in the progression of atherosclerosis. […] The hypoxia-induced activation of HIF-1 in macrophages may lead to the downregulation of PPAR-, thus driving plaque inflammation by reactivating proinflammatory genes and the repression of anti-inflammatory genes. […] Overall, these findings would suggest that hypoxia activates mTORC1 in macrophages, leading to plaque inflammation via NF-B and HIF-1 signalings. […] The binding and uptake of oxLDL by CD36 induce the activation of vimentin/FAK/NF-B axis in macrophages, resulting in cytokine release and inflammation. […] In summary, the described studies have shed light on the potential underlying mechanisms of macrophage-mediated inflammation after the exposure or uptake of oxLDL in atherosclerotic plaques.
#54 Pathophysiology of Atherosclerosis – Pathology
https://pressbooks.bccampus.ca/pathology/chapter/pathophysiology-of-atherosclerosis-and-angina/
Atherosclerosis develops as a result of a continuous process that involves endothelial activation, lipid accumulation, atheroma plaque formation, vascular remodeling, and ultimate narrowing of the blood vessel lumen. […] Atherosclerosis progression is initiated by endothelial activation in response to cardiovascular risk factors, such as hypertension, high blood glucose, smoking, increased cholesterol levels, etc. […] Some regions are more likely to form atherosclerotic plaques than others. This phenomenon can be partially explained by mechanical stress (wall shear stress, WSS) and type of blood flow (laminar vs turbulent). […] Turbulent flow and shear stress starts the process of atherosclerotic plaque formation by recruiting macrophages to enter the subendothelial space where they ingest oxidized LDL, becoming foam cells.
#55 Atherosclerosis: Symptoms, Causes & Treatment
https://my.clevelandclinic.org/health/diseases/16753-atherosclerosis-arterial-disease
Atherosclerosis involves gradual plaque buildup inside your artery. […] The stages of atherosclerosis happen over many years and include: Endothelial damage and immune response. Damage to your endothelium triggers chemical processes that cause white blood cells to travel to the injury site. These cells gather and lead to inflammation within your artery. Fatty streak formation. This is the first visible sign of atherosclerosis. Its a yellow streak or patch of dead foam cells at the site of endothelial damage. In this case, foam cells are white blood cells that consume cholesterol to try to get rid of it. Continued foam cell activity causes further damage to your endothelium. Plaque growth. Dead foam cells and other debris keep building up, turning a fatty streak into a larger piece of plaque. A fibrous cap (made of smooth muscle cells) forms over the plaque. This cap prevents bits of plaque from breaking off into your bloodstream. As the plaque grows, it gradually narrows your artery’s opening (lumen), so there’s less room for blood to flow through. Plaque rupture or erosion. In this stage, a blood clot forms in your artery due to plaque rupture or plaque erosion. Plaque rupture happens when the fibrous cap that covers the plaque breaks open. With plaque erosion, the fibrous cap stays intact, but endothelial cells around the plaque get worn away. Both events lead to the formation of a blood clot. The clot blocks blood flow and can lead to a heart attack or stroke.
#56 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
The necrotic core constitutes the nucleus of the atherosclerotic plaques. Covered by the fibrous cap, the necrotic core consists of a lipid-laden hipocellular region with reduced supporting collagen. […] Atheroma plaque calcification is another hallmark of advanced atherosclerosis. It exists as a bone-like formation within the plaque and is initiated in inflammatory regions with a local decrease in collagen fibers. […] A plaque is considered vulnerable when the lesion shows a large necrotic core, a thin fibrous cap, and an increased inflammatory response due to the continuous exposure to the pro-atherogenic milieu. […] When the plaque fissures or ruptures, the subendothelial space is exposed to blood, triggering a coagulation process to cover the wound.
#57 Pathophysiology of Atherosclerosis
https://www.mdpi.com/1422-0067/23/6/3346
Atherosclerosis is a disease that is characterized by the accumulation of lipids, fibrous elements, and calcification within the large arteries. This process is initiated by endothelium activation, followed by a cascade of events, which implies the vessel narrowing and activation of inflammatory pathways leading to atheroma plaque formation. […] The fibrous cap is a subendothelial barrier between the lumen of the vessel and the atherosclerotic necrotic core consisting of VSMCs that have migrated to the luminal side of the artery and extracellular matrix (ECM) derived from VSMCs. The role of the fibrous cap is to serve as a structural support to avoid the exposure of prothrombotic material of the core that otherwise would trigger thrombosis. […] The necrotic core constitutes the nucleus of the atherosclerotic plaques. Covered by the fibrous cap, the necrotic core consists of a lipid-laden hipocellular region with reduced supporting collagen.
#58 Atherosclerosis Pathology: Definition, Etiology, Epidemiology
https://emedicine.medscape.com/article/1612610-overview
Early lesion development is marked by lipid retention with activation of endothelial adhesion molecules. Inflammatory macrophages play a significant role throughout all phases of atherosclerotic progression; hyperlipidemia-induced macrophage infiltration of the arterial intima is one of the earliest pathologic changes. […] Studies suggest that the loss of smooth muscle cells (death by apoptosis) may be involved as their remnant basement membranes can be visualized by periodic acid-Schiff (PAS) staining and show microcalcification. […] The formation of lipid pools is associated with the infiltration and deposition of plasma-derived lipids. […] Intraplaque hemorrhage plays a pivotal role in the progression and destabilization of atherosclerotic plaques, significantly contributing to necrotic core expansion as red blood cells are a rich source of free cholesterol, which is an important constituent of ruptured plaques.
#59 Atherosclerosis Pathology: Definition, Etiology, Epidemiology
https://emedicine.medscape.com/article/1612610-overview
Early lesion development is marked by lipid retention with activation of endothelial adhesion molecules. Inflammatory macrophages play a significant role throughout all phases of atherosclerotic progression; hyperlipidemia-induced macrophage infiltration of the arterial intima is one of the earliest pathologic changes. […] Studies suggest that the loss of smooth muscle cells (death by apoptosis) may be involved as their remnant basement membranes can be visualized by periodic acid-Schiff (PAS) staining and show microcalcification. […] The formation of lipid pools is associated with the infiltration and deposition of plasma-derived lipids. […] Intraplaque hemorrhage plays a pivotal role in the progression and destabilization of atherosclerotic plaques, significantly contributing to necrotic core expansion as red blood cells are a rich source of free cholesterol, which is an important constituent of ruptured plaques.
#60 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
The necrotic core constitutes the nucleus of the atherosclerotic plaques. Covered by the fibrous cap, the necrotic core consists of a lipid-laden hipocellular region with reduced supporting collagen. […] Atheroma plaque calcification is another hallmark of advanced atherosclerosis. It exists as a bone-like formation within the plaque and is initiated in inflammatory regions with a local decrease in collagen fibers. […] A plaque is considered vulnerable when the lesion shows a large necrotic core, a thin fibrous cap, and an increased inflammatory response due to the continuous exposure to the pro-atherogenic milieu. […] When the plaque fissures or ruptures, the subendothelial space is exposed to blood, triggering a coagulation process to cover the wound.
#61 Pathophysiology of Atherosclerosis
https://www.mdpi.com/1422-0067/23/6/3346
Atheroma plaque calcification is another hallmark of advanced atherosclerosis. It exists as a bone-like formation within the plaque and is initiated in inflammatory regions with a local decrease in collagen fibers. […] A plaque is considered vulnerable when the lesion shows a large necrotic core, a thin fibrous cap, and an increased inflammatory response due to the continuous exposure to the pro-atherogenic milieu. […] When the plaque fissures or ruptures, the subendothelial space is exposed to blood, triggering a coagulation process to cover the wound.
#62 Atherosclerosis Pathology: Definition, Etiology, Epidemiology
https://emedicine.medscape.com/article/1612610-overview
The healing process involves thrombus lysis, granulation tissue formation, and reendothelialization, promoting plaque repair and vessel integrity. […] Studies have shown that certain conditions can influence plaque stability and healing. For instance, diabetes mellitus is associated with a higher incidence of HPRs and increased arterial calcification, indicating a more active atherogenic process.
#63 Atherosclerosis – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534258/
The aim of the present chapter is to summarize the data from a variety of research areas providing an overview of atherosclerosis focusing on mechanistic studies. […] Accumulating evidence suggests a causal relationship between blood cholesterol and atherosclerosis. […] LDL can be modified by oxidation in vivo and in vitro and is detectable in the circulation as well as in atherosclerotic lesions. […] The mechanism whereby hypercholesterolemia and oxidized-LDL trigger events leading to the generation of early atherosclerotic lesions i.e. fatty streak remains uncertain. […] The oxidative modification hypothesis has been extensively reviewed. […] The mechanism whereby mechanical forces are sensed by cells and transmitted through intracellular signal transduction pathways to the nucleus resulting in quantitative and qualitative changes in gene expression in the vessel wall is not fully understood.
#64 Atherosclerosis – Mechanisms of Vascular Disease – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK534258/
The aim of the present chapter is to summarize the data from a variety of research areas providing an overview of atherosclerosis focusing on mechanistic studies. […] Accumulating evidence suggests a causal relationship between blood cholesterol and atherosclerosis. […] LDL can be modified by oxidation in vivo and in vitro and is detectable in the circulation as well as in atherosclerotic lesions. […] The mechanism whereby hypercholesterolemia and oxidized-LDL trigger events leading to the generation of early atherosclerotic lesions i.e. fatty streak remains uncertain. […] The oxidative modification hypothesis has been extensively reviewed. […] The mechanism whereby mechanical forces are sensed by cells and transmitted through intracellular signal transduction pathways to the nucleus resulting in quantitative and qualitative changes in gene expression in the vessel wall is not fully understood.
#65 What is the role of lipids in atherosclerosis and how low should we decrease lipid levels?
https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/what-is-the-role-of-lipids-in-atherosclerosis-and-how-low-should-we-decrease-lip
According to the response-to-retention concept, the key initiating event in atherogenesis is the retention of these cholesterol-rich apoB-containing lipoproteins within the arterial wall, particularly in the presence of endothelial dysfunction. […] Following their retention in the arterial wall, lipoproteins undergo modifications and ultimately trigger a series of maladaptive responses that accelerate further lipoprotein retention and cause further plaque progression. […] In addition to facilitating uptake by macrophages and ultimately foam cell formation, oxidised LDL particles promote atherosclerosis via endothelial dysfunction, macrophage recruitment, enhanced platelet aggregation and thromboxane release, and increased apoptosis of smooth muscle cells and endothelial cells. […] Proatherogenic factors and enzymes that are released by monocytes/macrophages in the developing atheroma induce the formation of proteoglycans with great affinity to atherogenic lipoproteins, promoting a vicious circle that leads to further lipoprotein retention and progression of atherosclerosis.
#66 What is the role of lipids in atherosclerosis and how low should we decrease lipid levels?
https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/what-is-the-role-of-lipids-in-atherosclerosis-and-how-low-should-we-decrease-lip
According to the response-to-retention concept, the key initiating event in atherogenesis is the retention of these cholesterol-rich apoB-containing lipoproteins within the arterial wall, particularly in the presence of endothelial dysfunction. […] Following their retention in the arterial wall, lipoproteins undergo modifications and ultimately trigger a series of maladaptive responses that accelerate further lipoprotein retention and cause further plaque progression. […] In addition to facilitating uptake by macrophages and ultimately foam cell formation, oxidised LDL particles promote atherosclerosis via endothelial dysfunction, macrophage recruitment, enhanced platelet aggregation and thromboxane release, and increased apoptosis of smooth muscle cells and endothelial cells. […] Proatherogenic factors and enzymes that are released by monocytes/macrophages in the developing atheroma induce the formation of proteoglycans with great affinity to atherogenic lipoproteins, promoting a vicious circle that leads to further lipoprotein retention and progression of atherosclerosis.
#67 What is the role of lipids in atherosclerosis and how low should we decrease lipid levels?
https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/what-is-the-role-of-lipids-in-atherosclerosis-and-how-low-should-we-decrease-lip
According to the response-to-retention concept, the key initiating event in atherogenesis is the retention of these cholesterol-rich apoB-containing lipoproteins within the arterial wall, particularly in the presence of endothelial dysfunction. […] Following their retention in the arterial wall, lipoproteins undergo modifications and ultimately trigger a series of maladaptive responses that accelerate further lipoprotein retention and cause further plaque progression. […] In addition to facilitating uptake by macrophages and ultimately foam cell formation, oxidised LDL particles promote atherosclerosis via endothelial dysfunction, macrophage recruitment, enhanced platelet aggregation and thromboxane release, and increased apoptosis of smooth muscle cells and endothelial cells. […] Proatherogenic factors and enzymes that are released by monocytes/macrophages in the developing atheroma induce the formation of proteoglycans with great affinity to atherogenic lipoproteins, promoting a vicious circle that leads to further lipoprotein retention and progression of atherosclerosis.
#68 What is the role of lipids in atherosclerosis and how low should we decrease lipid levels?
https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/what-is-the-role-of-lipids-in-atherosclerosis-and-how-low-should-we-decrease-lip
According to the response-to-retention concept, the key initiating event in atherogenesis is the retention of these cholesterol-rich apoB-containing lipoproteins within the arterial wall, particularly in the presence of endothelial dysfunction. […] Following their retention in the arterial wall, lipoproteins undergo modifications and ultimately trigger a series of maladaptive responses that accelerate further lipoprotein retention and cause further plaque progression. […] In addition to facilitating uptake by macrophages and ultimately foam cell formation, oxidised LDL particles promote atherosclerosis via endothelial dysfunction, macrophage recruitment, enhanced platelet aggregation and thromboxane release, and increased apoptosis of smooth muscle cells and endothelial cells. […] Proatherogenic factors and enzymes that are released by monocytes/macrophages in the developing atheroma induce the formation of proteoglycans with great affinity to atherogenic lipoproteins, promoting a vicious circle that leads to further lipoprotein retention and progression of atherosclerosis.
#69 What is the role of lipids in atherosclerosis and how low should we decrease lipid levels?
https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/what-is-the-role-of-lipids-in-atherosclerosis-and-how-low-should-we-decrease-lip
In the pathogenesis of atherosclerosis, triglyceride-rich lipoproteins augment endothelial dysfunction, facilitate monocyte infiltration into the arterial wall, and increase activation of pro-inflammatory genes. […] The recommendations regarding target goals for LDL-C are based upon the principle that decreasing the concentration of apoB-containing lipoproteins in the circulation decreases the probability that they will enter and become retained in the subendothelium.
#70 Mechanism of Hypercholesterolemia-Induced Atherosclerosis
https://www.imrpress.com/journal/RCM/23/6/10.31083/j.rcm2306212/htm
Hypercholesterolemia is involved in the development of atherosclerosis and is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This paper deals with the mechanism of development of hypercholesterolemic atherosclerosis. Hypercholesterolemia increases the formation of numerous atherogenic biomolecules including reactive oxygen species (ROS), proinflammatory cytokines [interleukin (IL)-1, IL-2, IL-6, IL-8, tumor necrosis factor-alpha (TNF-Î±)], expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony stimulating factor (GM-CSF) and numerous growth factors [insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-1 (PDGF-1) and transforming growth factor-beta (TGF-Î²)]. ROS mildly oxidizes low-density lipoprotein-cholesterol (LDL-C) to form minimally modified LDL (MM-LDL) which is further oxidized to form oxidized LDL (OX-LDL). Hypercholesterolemia also activates nuclear factor-kappa-B (NF-ÎºB). The above atherogenic biomolecules are involved in the development of atherosclerosis which has been described in detail. Hypercholesterolemia also assists in the development of atherosclerosis through AGE (advanced glycation end-products)-RAGE (receptor for AGE) axis and C-reactive protein (CRP). Hypercholesterolemia is associated with increases in AGE, oxidative stress [AGE/sRAGE (soluble receptor for AGE)] and C-reactive protein, and decreases in the sRAGE, which are known to be implicated in the development of atherosclerosis. In conclusion, hypercholesterolemia induces atherosclerosis through increases in atherogenic biomolecules, AGE-RAGE axis and CRP.
#71 Mechanism of Hypercholesterolemia-Induced Atherosclerosis
https://www.imrpress.com/journal/RCM/23/6/10.31083/j.rcm2306212/htm
Hypercholesterolemia is involved in the development of atherosclerosis and is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This paper deals with the mechanism of development of hypercholesterolemic atherosclerosis. Hypercholesterolemia increases the formation of numerous atherogenic biomolecules including reactive oxygen species (ROS), proinflammatory cytokines [interleukin (IL)-1, IL-2, IL-6, IL-8, tumor necrosis factor-alpha (TNF-Î±)], expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony stimulating factor (GM-CSF) and numerous growth factors [insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-1 (PDGF-1) and transforming growth factor-beta (TGF-Î²)]. ROS mildly oxidizes low-density lipoprotein-cholesterol (LDL-C) to form minimally modified LDL (MM-LDL) which is further oxidized to form oxidized LDL (OX-LDL). Hypercholesterolemia also activates nuclear factor-kappa-B (NF-ÎºB). The above atherogenic biomolecules are involved in the development of atherosclerosis which has been described in detail. Hypercholesterolemia also assists in the development of atherosclerosis through AGE (advanced glycation end-products)-RAGE (receptor for AGE) axis and C-reactive protein (CRP). Hypercholesterolemia is associated with increases in AGE, oxidative stress [AGE/sRAGE (soluble receptor for AGE)] and C-reactive protein, and decreases in the sRAGE, which are known to be implicated in the development of atherosclerosis. In conclusion, hypercholesterolemia induces atherosclerosis through increases in atherogenic biomolecules, AGE-RAGE axis and CRP.
#72 Mechanism of Hypercholesterolemia-Induced Atherosclerosis
https://www.imrpress.com/journal/RCM/23/6/10.31083/j.rcm2306212/htm
Hypercholesterolemia is involved in the development of atherosclerosis and is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This paper deals with the mechanism of development of hypercholesterolemic atherosclerosis. Hypercholesterolemia increases the formation of numerous atherogenic biomolecules including reactive oxygen species (ROS), proinflammatory cytokines [interleukin (IL)-1, IL-2, IL-6, IL-8, tumor necrosis factor-alpha (TNF-Î±)], expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), granulocyte macrophage-colony stimulating factor (GM-CSF) and numerous growth factors [insulin-like growth factor-1 (IGF-1), platelet-derived growth factor-1 (PDGF-1) and transforming growth factor-beta (TGF-Î²)]. ROS mildly oxidizes low-density lipoprotein-cholesterol (LDL-C) to form minimally modified LDL (MM-LDL) which is further oxidized to form oxidized LDL (OX-LDL). Hypercholesterolemia also activates nuclear factor-kappa-B (NF-ÎºB). The above atherogenic biomolecules are involved in the development of atherosclerosis which has been described in detail. Hypercholesterolemia also assists in the development of atherosclerosis through AGE (advanced glycation end-products)-RAGE (receptor for AGE) axis and C-reactive protein (CRP). Hypercholesterolemia is associated with increases in AGE, oxidative stress [AGE/sRAGE (soluble receptor for AGE)] and C-reactive protein, and decreases in the sRAGE, which are known to be implicated in the development of atherosclerosis. In conclusion, hypercholesterolemia induces atherosclerosis through increases in atherogenic biomolecules, AGE-RAGE axis and CRP.
#73 Mechanism of Hypercholesterolemia-Induced Atherosclerosis
https://www.imrpress.com/journal/RCM/23/6/10.31083/j.rcm2306212/htm
Atherosclerosis affects medium and large-sized arteries and is characterized by focal thickening of the intima of the arteries and deposition of lipid, resulting in narrowing of the arteries. Atherosclerosis leads to cardiovascular diseases. There are numerous factors including hyperlipidemia, diabetes, hypertension, cigarette smoking, obesity, hyperhomocysteinemia, and elevated serum C-reactive protein which are involved in the development of atherosclerosis. […] Reactive oxygen species (ROS), and advanced glycation end products (AGE) and its cell receptor RAGE (receptor for AGE) and soluble receptor for AGE (sRAGE) have been implicated in the development of atherosclerosis. […] Hypercholesterolemia-induced atherosclerosis is based on the oxidative hypothesis of atherosclerosis which has been accepted universally. The proposed mechanism of atherosclerosis produced by hypercholesterolemia is depicted in Fig. 2. Hypercholesterolemia augments the production of ROS and cytokines which increase the expression of CAM in endothelial cells. The early step in the development of atherosclerosis is adherence of monocytes to endothelial cells and which is achieved through CAM. CAM is involved in the rolling and adhesion of monocytes to the endothelial cells. Monocyte then transmigrates into subendothelial space. MM-LDL produce monocyte chemoattractant protein-1 (MCP-1) in endothelial cells and vascular smooth muscle cells. The migration of monocytes to the subendothelial space is assisted by MCP-1. OX-LDL increases the expression of cell adhesion molecules. OX-LDL directly enhances the migration of monocytes to subendothelial space. Immigrating monocytes into the subendothelial space have LDL receptor but the rate of uptake of native LDL is not enough to produce foam cells. MM-LDL stimulates endothelial cells to express MC-SF that enhances the monocyte differentiation to form tissue macrophages which develop receptors for OX-LDL. OX-LDL is a ligand for scavenger receptors which are expressed in tissue macrophages. OX-LDL is taken up by tissue macrophage to form foam cells. Foam cells are involved in formation of numerous growth factors which enhance vascular smooth muscle cell proliferation and migration and fibrous tissue synthesis which helps in the development and progression of atherosclerosis. There is a development of fatty streaks in full-fledged atherosclerosis.
#74 Mechanism of Hypercholesterolemia-Induced Atherosclerosis
https://www.imrpress.com/journal/RCM/23/6/10.31083/j.rcm2306212/htm
Hypercholesterolemia increases the production of ROS which sets the stage for the production of other atherogenic biomolecules leading to the formation of atherosclerosis. Reduction in antioxidant enzymes by high blood cholesterol would also elevate the ROS levels. Hypercholesterolemia-induced atherosclerosis is associated with increases in the serum/plasma/tissue levels of direct and indirect measures of ROS. Blockade of the ROS with antioxidant (vitamin E), hypolipidemic and antioxidant agents (SDG, flax lignan complex, and probucol), cyclooxygenase inhibitors (aspirin) and indomethacin, and inhibitors of cytokines and PAF (pentoxifylline) decreased the development of hypercholesterolemic atherosclerosis and amount of ROS. The above data indicate that there is an association between hypercholesterolemic atherosclerosis and ROS, while lowering the serum cholesterol and blockade of sources ROS reduces the extent of atherosclerosis and ROS. It is to note that hypercholesterolemia elevates the serum levels of AGE and AGE/sRAGE, and lowers the serum levels of sRAGE. An increase in AGE and AGE/sRAGE, and a decrease in sRAGE in the serum have been implicated in the development of atherosclerosis. Hypercholesterolemia has been reported to elevate the serum levels of CRP in human subjects. A rise in C-reactive protein increases the serum levels of atherogenic biomolecules and induces development of atherosclerosis. Hypercholesterolemia induces atherosclerosis through increases in the atherogenic biomolecules (ROS, NADPH-oxidase, NF-ÎºB, CAM, MCP-1, GM-CSF, cytokines, MM-LDL, OX-LDL and growth factors). The initiating atherogenic biomolecule is ROS.
#75 PATHOLOGY – Arteriosclerosis | PPT
https://www.slideshare.net/slideshow/pathology-arteriosclerosis-15120998/15120998
Atherosclerosis is characterized by chronic inflammation of an injured intima. […] Atherosclerosis is the accumulation of inflammatory cells, lipids, and connective tissue in the intima of large and medium arteries, forming fibroinflammatory plaques known as atheromas. […] It develops over decades as a response to endothelial injury from risk factors like hypercholesterolemia and hypertension. […] Complicated plaques can rupture, causing thrombosis, embolism, and occlusion of vessels, leading to complications like myocardial infarction.
#76 Novel Insights into the Molecular Mechanisms of Atherosclerosis
https://www.mdpi.com/1422-0067/24/17/13434
Atherosclerosis results in CVD, which can take the form of ischemic heart disease, stroke, or other vascular diseases. […] Atherosclerosis is chronic arterial inflammation caused by both conventional and unconventional risk factors that result in plaque development in the vascular intima. […] The most crucial recommendations for the prevention of atherosclerosis include a proper diet, physical exercise, smoking cessation, adequate stress management, and good quality of sleep. […] Aging is one of the strongest risk factors for atherosclerosis which increases the morbidity and mortality of patients. […] The vascular endothelium plays a regulatory role in vascular muscle contraction, relaxation, smooth muscle proliferation, and the expression of adhesion molecules or chemotactic factors.
#77 Novel Insights into the Molecular Mechanisms of Atherosclerosis
https://www.mdpi.com/1422-0067/24/17/13434
Endothelial dysfunction occurs under the influence of many factors, including local hemodynamic changes. […] Elevated serum UA is linked to various negative consequences, such as hypertension, chronic kidney diseases, and CVDs. […] Recent experimental and clinical studies showed evidence for the effect of vit. D signaling on the modulation of atherosclerosis pathogenesis. […] MicroRNAs (miRNAs) are small non-coding RNAs that have diverse cellular roles but are best known for silencing and fine-tuning the expression of messenger RNA (mRNA) transcripts. […] The development of atherosclerosis is accelerated by oxidative stress, which stimulates hyperuricemia. […] These findings might shed new light on the cellular mechanisms of atherosclerosis and prospective targets for prevention and treatment in the future.
#78 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Accumulation of LDL in plasma favors transendothelial infiltration of circulating LDLs to the intima. […] Once in the subendothelial space, trapped LDL particles are oxidized, a process facilitated by the absence of protective plasma antioxidants, such as tocopherol, ascorbate, urate, apolipoproteins, or serum albumin. Oxidized LDLs are key inflammatory components that promote atherosclerotic plaque development, as they contain oxidized lipids and products derived from their degradation that contribute to the physiopathology of the disease. […] Endothelial stimulation, also known as endothelial type I activation, occurs when inflammatory agents induce a response such as a change in microvascular tone, permeability, or leukocyte diapedesis. […] Activated ECs induce selective monocyte recruitment into the intima.
#79 Pathophysiology of Atherosclerosis
https://pmc.ncbi.nlm.nih.gov/articles/PMC8954705/
Accumulation of LDL in plasma favors transendothelial infiltration of circulating LDLs to the intima. […] Once in the subendothelial space, trapped LDL particles are oxidized, a process facilitated by the absence of protective plasma antioxidants, such as tocopherol, ascorbate, urate, apolipoproteins, or serum albumin. Oxidized LDLs are key inflammatory components that promote atherosclerotic plaque development, as they contain oxidized lipids and products derived from their degradation that contribute to the physiopathology of the disease. […] Endothelial stimulation, also known as endothelial type I activation, occurs when inflammatory agents induce a response such as a change in microvascular tone, permeability, or leukocyte diapedesis. […] Activated ECs induce selective monocyte recruitment into the intima.
#80 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. […] Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. […] Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. […] The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. […] A process similar to bone formation causes calcification within the plaque.
#81 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. […] Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. […] Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. […] The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. […] A process similar to bone formation causes calcification within the plaque.
#82 Atherosclerosis – Cardiovascular Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/cardiovascular-disorders/arteriosclerosis/atherosclerosis
Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. […] Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. […] Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. […] The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. […] A process similar to bone formation causes calcification within the plaque.
#83 Inflammation in atherosclerosis: pathophysiology and mechanisms | Cell Death & Disease
https://www.nature.com/articles/s41419-024-07166-8
Inflammatory macrophages release chemokines/cytokines, which promote plaque inflammation. […] As the plaque grows, it becomes unstable and may rupture. […] Due to the inflammatory milieu of the plaque, procoagulant factors are activated and fibrin production increases. […] While efferocytosis prevents inflammation and plaque growth, the impaired efferocytosis of apoptotic/necrotic bodies may lead to further deposition of macrophages/foam cells in the plaque. […] The oxidation of LDL promotes its uptake by macrophages in the intimal layer. […] Hence, beyond the primary events, inflammation plays a decisive role in the exacerbation of the plaque and the progression of atherosclerosis. […] Stable plaques are featured by chronic low-grade inflammation, while unstable plaques exhibit active inflammation, which further promotes plaque rupture and vulnerability by thinning the fibrous cap.
#84 Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease: Implications for Evaluation and Targets for Treatment of Dyslipidemia Based on Recent Guidelines | IntechOpen
https://www.intechopen.com/chapters/66725
With continued endothelial compromise in regions of arterial curvature and bifurcation, circulating LDL, and to a lesser degree VLDL and IDL, increasingly migrate from the plasma and are retained in the extracellular matrix of the tunica intima. […] Subendothelial accumulation of LDL and VLDL remnants precipitates endothelial activation of the nuclear factor kappa B (NF-B) pathway that enhances endothelial expression of adhesion proteins such as VCAM-1 and P-selection and pro-inflammatory receptors and cytokines that promote monocyte migration. […] Despite the predominance of LDL in the cycle of endothelial damage, macrophage absorption, foam cell formation, and inflammatory transduction, VLDL and Lp(a) play important roles in endothelial activation. […] The cascade of endothelial dysfunction, lipoprotein accumulation, and inflammatory pathways results in dramatic changes in VSMC physiology.
#85 Pathophysiology of Atherosclerosis – Pathology
https://pressbooks.bccampus.ca/pathology/chapter/pathophysiology-of-atherosclerosis-and-angina/
Atherosclerosis plaque formation begins with activation and/or damage to the endothelium, which disrupts the normal process of LDL intake and metabolism. […] Oxidized LDL (oxLDL) is a key inflammatory component that facilitates atherosclerosis progression. […] These initial processes create a vicious circle that results in further recruitment of monocytes, LDL retention, and oxLDL accumulation. […] As the vicious circle progresses, LDL is deposited both inside cells and in the extracellular matrix, and cholesterol crystals form. […] Foam cells (derived from macrophages and VSMCs) undergo cellular death (apoptosis) and release their contents within the tunica intima. […] In response to the atherosclerotic lesion progression, more VSMCs are recruited from the tunica media to the intima to form a fibrous cap a protective layer that covers the necrotic core.
#86 Pathophysiology of Atherosclerosis – Pathology
https://pressbooks.bccampus.ca/pathology/chapter/pathophysiology-of-atherosclerosis-and-angina/
The thickness of the fibrous cap covering the soft necrotic core of an atherosclerotic lesion, as well as its composition (the amount of collagen/elastin fibers), affect the stability of the plaque and clinical outcomes. […] Atherosclerotic plaques can become more vulnerable if VSMCs within the fibrous cap respond to inflammation by producing enzymes that degrade components of the extracellular matrix, weakening the fibrous cap and making it more susceptible to rupture.
#87 Pathophysiology of Atherosclerosis – Pathology
https://pressbooks.bccampus.ca/pathology/chapter/pathophysiology-of-atherosclerosis-and-angina/
The thickness of the fibrous cap covering the soft necrotic core of an atherosclerotic lesion, as well as its composition (the amount of collagen/elastin fibers), affect the stability of the plaque and clinical outcomes. […] Atherosclerotic plaques can become more vulnerable if VSMCs within the fibrous cap respond to inflammation by producing enzymes that degrade components of the extracellular matrix, weakening the fibrous cap and making it more susceptible to rupture.
#88 Novel Insights into the Molecular Mechanisms of Atherosclerosis
https://www.mdpi.com/1422-0067/24/17/13434
Atherosclerosis results in CVD, which can take the form of ischemic heart disease, stroke, or other vascular diseases. […] Atherosclerosis is chronic arterial inflammation caused by both conventional and unconventional risk factors that result in plaque development in the vascular intima. […] The most crucial recommendations for the prevention of atherosclerosis include a proper diet, physical exercise, smoking cessation, adequate stress management, and good quality of sleep. […] Aging is one of the strongest risk factors for atherosclerosis which increases the morbidity and mortality of patients. […] The vascular endothelium plays a regulatory role in vascular muscle contraction, relaxation, smooth muscle proliferation, and the expression of adhesion molecules or chemotactic factors.
#89 Atherosclerosis – Wikipedia
https://en.wikipedia.org/wiki/Atherosclerosis
Chronic inflammation within the arterial wall, driven by immune cells like macrophages, accelerates atherosclerotic plaque instability by promoting collagen breakdown and thinning the fibrous cap, which increases the likelihood of rupture and thrombosis. […] The primary documented driver of this process is oxidized lipoprotein particles within the wall, beneath the endothelial cells, though upper normal or elevated concentrations of blood glucose also plays a major role and not all factors are fully understood.
#90 Atherosclerosis – Wikipedia
https://en.wikipedia.org/wiki/Atherosclerosis
Chronic inflammation within the arterial wall, driven by immune cells like macrophages, accelerates atherosclerotic plaque instability by promoting collagen breakdown and thinning the fibrous cap, which increases the likelihood of rupture and thrombosis. […] The primary documented driver of this process is oxidized lipoprotein particles within the wall, beneath the endothelial cells, though upper normal or elevated concentrations of blood glucose also plays a major role and not all factors are fully understood.
#91 Dyslipidemia and Its Role in the Pathogenesis of Atherosclerotic Cardiovascular Disease: Implications for Evaluation and Targets for Treatment of Dyslipidemia Based on Recent Guidelines | IntechOpen
https://www.intechopen.com/chapters/66725
The nonresolving inflammatory processes of lipoprotein accumulation, foam cell formation, and immunologic activation leads to fibrocellular organization of the plaque, with the plaque becoming increasingly unstable and prone to rupture and acute thrombosis via fibrous cap thinning and lipid necrotic core expansion. […] Atherosclerotic cardiovascular disease encompasses conditions carrying tremendous morbidity and mortality, and is the acute and chronic clinical manifestations of a progressive pathogenic process that is initiated by the inflammatory responses to dyslipidemia.
#92 Atherosclerosis ppt | PPT
https://www.slideshare.net/slideshow/atherosclerosis-ppt/30403631
Atherosclerosis develops as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T-lymphocytes, and the normal cellular constituent of the arterial wall. The contemporary view of atherosclerosis is expressed by the response-to-injury hypothesis. […] Atherosclerosis starts with damage or injury to the inner layer of an artery. The damage may be caused by: High blood pressure, High cholesterol, An irritant, such as nicotine, Certain diseases, such as diabetes. […] Atherosclerosis is a preventable and treatable condition. […] Atherosclerosis symptoms depend on which arteries are affected. For example: Atherosclerosis in heart arteries, have symptoms similar to those of a heart attack, such as chest pain (angina). Atherosclerosis in the arteries leading to brain, have symptoms such as sudden numbness or weakness in your arms or legs, difficulty speaking or slurred speech, or drooping muscles in your face.
#93 Atherosclerosis ppt | PPT
https://www.slideshare.net/slideshow/atherosclerosis-ppt/30403631
Atherosclerosis develops as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T-lymphocytes, and the normal cellular constituent of the arterial wall. The contemporary view of atherosclerosis is expressed by the response-to-injury hypothesis. […] Atherosclerosis starts with damage or injury to the inner layer of an artery. The damage may be caused by: High blood pressure, High cholesterol, An irritant, such as nicotine, Certain diseases, such as diabetes. […] Atherosclerosis is a preventable and treatable condition. […] Atherosclerosis symptoms depend on which arteries are affected. For example: Atherosclerosis in heart arteries, have symptoms similar to those of a heart attack, such as chest pain (angina). Atherosclerosis in the arteries leading to brain, have symptoms such as sudden numbness or weakness in your arms or legs, difficulty speaking or slurred speech, or drooping muscles in your face.