Atherosclerosis - Wikipedia
Unresolved inflammation results in formation of vulnerable plaques characterized Non-HDL cholesterol levels capture all of the apoB containing lipoproteins The relationship between LDL-C levels and risk for ASCVD is. When plaque (fatty deposits) clogs your arteries, that's called atherosclerosis. These deposits are made up of cholesterol, fatty substances, cellular waste. The LDL particle has a core that is mostly composed of cholesterol plaque formation and increasingly deposits with plaque growth (18).
At first, as the plaques grow, only wall thickening occurs without any narrowing. Stenosis is a late event, which may never occur and is often the result of repeated plaque rupture and healing responses, not just the atherosclerotic process by itself. Cellular[ edit ] Micrograph of an artery that supplies the heart showing significant atherosclerosis and marked luminal narrowing.
Tissue has been stained using Masson's trichrome. Early atherogenesis is characterized by the adherence of blood circulating monocytes a type of white blood cell to the vascular bed lining, the endotheliumthen by their migration to the sub-endothelial space, and further activation into monocyte-derived macrophages.
Fatty streaks may appear and disappear. Low-density lipoprotein LDL particles in blood plasma invade the endothelium and become oxidized, creating risk of cardiovascular disease. A complex set of biochemical reactions regulates the oxidation of LDL, involving enzymes such as Lp-LpA2 and free radicals in the endothelium.
Initial damage to the endothelium results in an inflammatory response. Monocytes enter the artery wall from the bloodstream, with platelets adhering to the area of insult. This may be promoted by redox signaling induction of factors such as VCAM-1which recruit circulating monocytes, and M-CSFwhich is selectively required for the differentiation of monocytes to macrophages.
The monocytes differentiate into macrophageswhich proliferate locally,  ingest oxidized LDL, slowly turning into large " foam cells " — so-called because of their changed appearance resulting from the numerous internal cytoplasmic vesicles and resulting high lipid content.
Under the microscope, the lesion now appears as a fatty streak. Foam cells eventually die and further propagate the inflammatory process. In addition to these cellular activities, there is also smooth muscle proliferation and migration from the tunica media into the intima in response to cytokines secreted by damaged endothelial cells.
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This causes the formation of a fibrous capsule covering the fatty streak. Intact endothelium can prevent this smooth muscle proliferation by releasing nitric oxide.
Calcification and lipids[ edit ] Calcification forms among vascular smooth muscle cells of the surrounding muscular layer, specifically in the muscle cells adjacent to atheromas and on the surface of atheroma plaques and tissue. With the atheromatous plaque interfering with the regulation of the calcium deposition, it accumulates and crystallizes. A similar form of an intramural calcification, presenting the picture of an early phase of arteriosclerosis, appears to be induced by a number of drugs that have an antiproliferative mechanism of action Rainer Liedtke Cholesterol is delivered into the vessel wall by cholesterol-containing low-density lipoprotein LDL particles.
To attract and stimulate macrophages, the cholesterol must be released from the LDL particles and oxidized, a key step in the ongoing inflammatory process. The process is worsened if there is insufficient high-density lipoprotein HDLthe lipoprotein particle that removes cholesterol from tissues and carries it back to the liver. The foam cells and platelets encourage the migration and proliferation of smooth muscle cells, which in turn ingest lipids, become replaced by collagen and transform into foam cells themselves.
A protective fibrous cap normally forms between the fatty deposits and the artery lining the intima. These capped fatty deposits now called 'atheromas' produce enzymes that cause the artery to enlarge over time.
As long as the artery enlarges sufficiently to compensate for the extra thickness of the atheroma, then no narrowing " stenosis " of the opening "lumen" occurs. The artery becomes expanded with an egg-shaped cross-section, still with a circular opening. If the enlargement is beyond proportion to the atheroma thickness, then an aneurysm is created. Although arteries are not typically studied microscopically, two plaque types can be distinguished: Beneath the endothelium there is a "fibrous cap" covering the atheromatous "core" of the plaque.
The core consists of lipid-laden cells macrophages and smooth muscle cells with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits released from dead cellswhich form areas of cholesterol crystals with empty, needle-like clefts.
At the periphery of the plaque are younger "foamy" cells and capillaries. These plaques usually produce the most damage to the individual when they rupture. Cholesterol crystals may also play a role. The fibrous plaque contains collagen fibers eosinophilicprecipitates of calcium hematoxylinophilic and, rarely, lipid-laden cells. In effect, the muscular portion of the artery wall forms small aneurysms just large enough to hold the atheroma that are present.
The muscular portion of artery walls usually remain strong, even after they have remodeled to compensate for the atheromatous plaques. However, atheromas within the vessel wall are soft and fragile with little elasticity. Arteries constantly expand and contract with each heartbeat, i. In addition, the calcification deposits between the outer portion of the atheroma and the muscular wall, as they progress, lead to a loss of elasticity and stiffening of the artery as a whole.
The calcification deposits,  after they have become sufficiently advanced, are partially visible on coronary artery computed tomography or electron beam tomography EBT as rings of increased radiographic density, forming halos around the outer edges of the atheromatous plaques, within the artery wall.
These deposits demonstrate unequivocal evidence of the disease, relatively advanced, even though the lumen of the artery is often still normal by angiography.
Rupture and stenosis[ edit ] Progression of atherosclerosis to late complications. Although the disease process tends to be slowly progressive over decades, it usually remains asymptomatic until an atheroma ulcerateswhich leads to immediate blood clotting at the site of atheroma ulcer.
This triggers a cascade of events that leads to clot enlargement, which may quickly obstruct the flow of blood. A complete blockage leads to ischemia of the myocardial heart muscle and damage. This process is the myocardial infarction or "heart attack". If the heart attack is not fatal, fibrous organization of the clot within the lumen ensues, covering the rupture but also producing stenosis or closure of the lumen, or over time and after repeated ruptures, resulting in a persistent, usually localized stenosis or blockage of the artery lumen.
Repeated plaque ruptures, ones not resulting in total lumen closure, combined with the clot patch over the rupture and healing response to stabilize the clot is the process that produces most stenoses over time.
The stenotic areas tend to become more stable despite increased flow velocities at these narrowings. Most major blood-flow-stopping events occur at large plaques, which, prior to their rupture, produced very little if any stenosis.
Most severe clinical events do not occur at plaques that produce high-grade stenosis. These tissue fragments are very clot-promoting, containing collagen and tissue factor ; they activate platelets and activate the system of coagulation.
The result is the formation of a thrombus blood clot overlying the atheroma, which obstructs blood flow acutely. With the obstruction of blood flow, downstream tissues are starved of oxygen and nutrients. If this is the myocardium heart muscle angina cardiac chest pain or myocardial infarction heart attack develops.
Accelerated growth of plaques[ edit ] The distribution of atherosclerotic plaques in a part of arterial endothelium is inhomogeneous. Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis. Arterial injury causes endothelial dysfunction promoting modification of apoB containing lipoproteins and infiltration of monocytes into the subendothelial space.
Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis.
HDL, apoA-I, and endogenous apoE prevent inflammation and oxidative stress and promote cholesterol efflux to reduce lesion formation. Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells. Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets. Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells resulting in necrotic cell death leading to increased smooth cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases.
Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE. Surprisingly, native LDL is not taken up by macrophages in vitro but has to be modified to promote foam cell formation. Oxidative modification converts LDL into atherogenic particles that initiate inflammatory responses. Uptake and accumulation of oxidatively modified LDL oxLDL by macrophages initiates a wide range of bioactivities that may drive development of atherosclerotic lesions.
Lowering LDL-cholesterol with statins reduces risk for cardiovascular events, providing ultimate proof of the cholesterol hypothesis.
All of the apoB containing lipoproteins are atherogenic, and both triglyceride rich remnant lipoproteins and Lp a promote atherothrombosis. Non-HDL cholesterol levels capture all of the apoB containing lipoproteins in one number and are useful in assessing risk in the setting of hypertriglyceridemia.
Here, we also describe the current landscape of HDL metabolism. Furthermore, we describe many beneficial properties of HDL that antagonize atherosclerosis and how HDL dysfunction may promote cardiometabolic disease.
The discovery by Virchow more than years ago that atheroma contained a yellow fatty substance, later identified as cholesterol by Windaus, suggested a role for lipids in the pathogenesis of atherosclerosis2. Indeed, the goal of this chapter is to focus on the role of lipids and lipoproteins in the pathogenesis of atherosclerosis as well as their critical roles in risk assessment and as targets of therapy.
The recognition that atherosclerosis is an inflammatory disease Figure 1 Initiation of the atherosclerotic lesion. The fatty streak phase of atherosclerosis begins with dysfunctional endothelial cells and the retention of apoB-containing lipoproteins LDL, VLDL, and apoE remnants in the subendothelial space. Retained lipoproteins are modified oxidation, glycation, enzymaticwhich, along with other atherogenic factors, promotes activation of endothelial cells.
Activated endothelial cells also promote the recruitment of other immune cells including dendritic cells, mast cells, regulatory T T-reg cells, and T helper 1 Th-1 cells.
The monocytes differentiate into macrophages and express receptors that mediate the internalization of VLDL, apoE remnants, and modified LDL to become foam cells. In addition, inflammatory signaling pathways are activated in macrophage foam cells leading to more cell recruitment and LDL modification. First, we provide brief description of the cellular and molecular events in the key stages of atherosclerosis.
Initiation and Fatty Streak Phase of Atherosclerotic Lesions The endothelial lining of arteries responds to mechanical and molecular stimuli to regulate tone,4 hemostasis,5 and inflammation6 throughout the circulation.
Endothelial cell dysfunction is an initial step in atherosclerotic lesion formation and is more likely to occur at arterial curves and branches that are subjected to low shear stress and disturbed blood flow atherosclerosis prone areas 7, 8.
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These mechanical stimuli activate signaling pathways leading to a dysfunctional endothelium lining that is barrier compromised, prothrombotic, and proinflammatory9.
In atherosclerosis susceptible regions, the endothelial cells have cuboidal morphology, a thin glycocalyx layer, and a disordered alignment8, 10, In addition, these regions have increased endothelial cell senescence and apoptosis as evidenced by ER stress markers In contrast, less atherosclerosis prone endothelium is exposed to laminar shear stress causing activation of signaling pathways that maintain endothelial cell coaxial alignment, proliferation,13, 14 glycocalyx layer,15 and survival12, The increased nitric oxide NO production promotes endothelial cell migration and survival thereby maintaining an effective barrier In addition, the expression of superoxide dismutase SOD is increased to reduce cellular oxidative stress In atherosclerosis susceptible regions, reduced expression of eNOS and SOD leads to compromised endothelial barrier integrity Figure 1leading to increased accumulation and retention of subendothelial atherogenic apolipoprotein B apoB -containing lipoproteins low-density lipoproteins LDL and remnants of very low-density lipoproteins VLDL and chylomicrons 21, In addition, endothelial cell activation leads to increased production of reactive oxygen species25 that can cause oxidative modification of apoB-containing lipoproteins Besides mechanical stimuli, endothelial cell activation is increased by various molecular stimuli, including oxidized LDL, cytokines, advanced glycosylation end products, and pathogen-associated molecules In contrast, an atheroprotective function of HDL is to prevent endothelial activation and enhance NO production to maintain barrier integrity see details below Monocyte Recruitment and Foam Cell Formation Activation of endothelial cells causes a monocyte recruitment cascade involving rolling, adhesion, activation and transendothelial migration Figure 1.
Selectins, especially P-selectin, mediate the initial rolling interaction of monocytes with the endothelium Potent chemoattractant factors such as MCP-1 and IL-8 then induce migration of monocytes into the subendothelial space Ly6hi monocytes, versus Ly6lo, preferentially migrate into the subendothelial space to convert to proinflammatory macrophages in mice The enhanced migration of Ly6hi versus Ly6lo monocytes likely results from increased expression of functional P-selectin glycoprotein ligand In addition, the number of blood monocytes originating from the bone marrow and spleen, especially Ly6hi cells, increases in response to hypercholesterolemia Although macrophages are the main infiltrating cells, other cells contribute to development of lesions including dendritic cells41, 42 mast cells and T cells Figure 1 43, T cells regulate the proinflammatory phenotype of macrophages.
Antigen-specific activated T helper 1 Th-1 cells produce interferon IFN that converts macrophages to a proinflammatory M1 phenotype.
During the initial fatty streak phase of atherosclerosis Figure 1the monocyte-derived macrophages internalize the retained apoB-containing lipoproteins, which are degraded in lysosomes, where excess free cholesterol is trafficked to the endoplasmic reticulum ER to be esterified by acyl CoA: Modification of apoB lipoproteins via oxidation and glycation enhances their uptake through a number of receptors not down-regulated by cholesterol including CD36, scavenger receptor A, and lectin-like receptor family see details below Figure 2 47, Enzyme-mediated aggregation of apoB lipoproteins enhances uptake via phagocytosis Figure 2 49, The LDL is endocytosed and trafficked to lysosomes, where the cholesteryl ester CE is hydrolyzed to free cholesterol FC by the acid lipase.
Cholesterol regulation of the LDLR prevents foam cell formation via this receptor in the setting of hypercholesterolemia. Uptake of native LDL by fluid phase pinocytosis may also contribute to foam cell formation. Modifications of apoB containing lipoproteins induce significant cholesterol accumulation via a number of mechanisms.
Enzyme-mediated aggregation of apoB lipoproteins enhances uptake via phagocytosis. Cytoplasmic CE is cleared by two main pathways. In one pathway, removal of FC from the plasma membrane stimulates transport of FC that has been generated by neutral cholesterol esterase away from ACAT to the plasma membrane.
Alternatively, cytoplasmic CE is packaged into autophagosomes, which are transported to fuse with lysosomes, where the CE is hydrolyzed by acid lipase and the resulting FC is then transported to the plasma membrane.
The efflux of FC to lipid-poor apolipoproteins or HDL occurs by a number of mechanisms to reduce foam cell formation. ApoE produces the most buoyant, FC-enriched particles. ABCG1 may also play a role in the intracellular trafficking of cholesterol. Figure 2 51, Uptake of native LDL by fluid phase pinocytosis may also contribute to foam cell formation Figure 2 53, The triggering of macrophage inflammatory pathways is also a critical event in lesion development.
Oxidative stress, modified lipoproteins, and other lesion factors bioactive lipids, pattern recognition molecules, cytokines are capable of inducing inflammation via receptors55, 56, In addition, plasma membrane cholesterol in macrophage foam cells enhances signaling via inflammatory receptors62, Cytoplasmic CE is cleared by two major pathways.
Alternatively, cytoplasmic CE is packaged into autophagosomes, which are trafficked to lysosomes, where the CE is hydrolyzed by acid lipase73, 74, generating free cholesterol that is made available for efflux mainly via ABCA1 Figure 2 73, Furthermore, HDL and apoA-I protect against atherosclerosis by reducing inflammation via mechanisms independent of cholesterol efflux31, 75 see details below. ApoE serves as the ligand for clearance of all of the apoB containing lipoproteins from the blood by the liver except for LDL.
Gene knockout of apoE in mice results in hypercholesterolemia and spontaneous atherosclerotic lesion development 77, Hence, ApoE deficient mice have been used widely to study mechanisms of atherosclerotic lesion development.
Bone marrow transplantation studies were used to examine the role of macrophage apoE in lipoprotein metabolism. Interestingly, ApoE protects against atherosclerosis via several mechanisms. Expression of apoE by hematopoietic stem cells reduces monocyte proliferation and infiltration into the intima In addition, apoE on apoB lipoproteins reduces the lysosomal accumulation of cholesterol by enhancing the expression of acid lipase Importantly, secretion of apoE by macrophages stimulates efflux in the absence and presence of exogenous acceptors, including HDL and lipid-free apoA-I Figure 2 Recent studies demonstrated that macrophage apoE facilitates reverse cholesterol transport in vivo Endogenous apoE is required for efficient formation of the most buoyant, cholesterol-enriched particles by macrophages Figure 2 84, In addition to cholesterol efflux, macrophage apoE prevents inflammation and oxidative stress The local production of apoE is likely a critical atheroprotective mechanism considering that areas of atherosclerotic lesions have limited accessibility to plasma apoA-1 and HDL80, 81, Humans express three common apoE polymorphisms that predict CAD rates independently from plasma cholesterol levels ApoE3 C, R is the most common isoform and is functionally similar to mouse apoE.
Compared to apoE3 and apoE2 C, CapoE4 R, R are impaired in stimulating cholesterol efflux and in preventing inflammation and oxidation 97, Consistent with the compromised function of apoE4, human carriers exhibit increased risk of CAD compared to humans expressing apoE3 or apoE2 heterozygous, Figure 3 Progression of the atherosclerotic plaque.
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Macrophage foam cell and endothelial cell inflammatory signaling continues to promote the recruitment of more monocytes and immune cells into the subendothelial space. Transition from a fatty streak to a fibrous fatty lesion occurs with the infiltration and proliferation of tunica media smooth muscle cells. Smooth muscle cells are recruited to the luminal side of the lesion to proliferate and generate an extracellular matrix network to form a barrier between lesional prothrombotic factors and blood platelets and procoagulant factors.
A subset of smooth muscle cells express macrophage receptors and internalize lipoproteins to become foam cells. Fibrous fatty lesions are less likely to regress than fatty streaks. Progression to Advanced Atherosclerotic Lesions Fatty streaks do not result in clinical complications and can even undergo regression.
However, once smooth muscle cells infiltrate, and the lesions become more advanced, regression is less likely to occur, Small populations of vascular smooth muscle cells VSMCs already present in the intima proliferate in response to growth factors produced by inflammatory macrophages In addition, macrophage-derived chemoattractants cause tunica media smooth muscle cells to migrate into the intima and proliferate Figure 3. Critical smooth muscle cell chemoattractants and growth factors include PDGF isoforms, matrix metalloproteinases, fibroblast growth factors, and heparin-binding epidermal growth factor Figure 3 HDL prevents smooth muscle cell chemokine production and proliferation.
The accumulating VSMCs produce a complex extracellular matrix composed of collagen, proteoglycans, and elastin to form a fibrous cap over a core comprised of foam cells Figure 4