Cholesterol and relationship to plaque formation

LDL Cholesterol and Heart Disease | Berkeley Wellness

cholesterol and relationship to plaque formation

Atherosclerosis is a lipoprotein-driven disease that leads to plaque formation at specific . Relationship of baseline serum cholesterol levels in 3 large cohorts of . When plaque (fatty deposits) clogs your arteries, that's called atherosclerosis. These deposits are made up of cholesterol, fatty substances, cellular waste. Low density lipoprotein (LDL) cholesterol enters dysfunctional endothelium ( which is damaged by smoking or diabetes, for example, and this is.

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.

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 A vital component of the fibrous cap is collagen, and macrophage-derived TGF- stimulates its production Figure 4 In addition, HDL maintains plaque stability by inhibiting degradation of the fibrous cap extracellular matrix through its anti-elastase activity This smooth muscle cell phenotype produces less -actin and expresses macrophage markers, including CD68 and Mac, While studies have shown that VSMCs express the VLDL receptor and various scavenger receptors, data showing that these cells robustly load with CE, similar to macrophages via these mechanisms is lacking.

As lesions advance, substantial extracellular lipid accumulates in the core, in part due to large CE-rich particles arising from dead macrophage foam cells, Regardless of the mechanisms of cholesterol enrichment, VSMCs compared to macrophages are inefficient at lysosomal processing and trafficking of cholesterol, and express much less ABCA, which all contribute to impaired cholesterol efflux However, macrophages in more advanced plaques also have reduced lysosome function and trapping of free and esterified cholesterol within their lysosomes contributes to the overall sterol accumulation in the lesion The reduced lysosome function appears multifactoral but includes direct and indirect inhibition of lysosomal acid lipase, the enzyme responsible for hydrolysis of cholesteryl esters in lysosomes, and a reduced capacity for transferring cholesterol from lysosomes In cell culture models of human macrophage foam cells, the inability to clear cholesterol from macrophages with compromised lysosome function continues even in the presence of compounds that stimulate efflux, Proteomic analysis of foam cells shows that changes in a number of lysosome proteases are related to macrophage sterol accumulation Thus, at least in the advanced stages of atherosclerosis, lysosome dysfunction contributes to the overall lesion severity.

As the intimal volume enlarges due to accumulating cells, there is vascular remodeling to lessen protrusion of the lesion into the lumen Figure 4thereby decreasing occlusion and the appearance of clinical symptoms for much of the life of the lesion Figure 4 Features of the stable fibrous plaque.

As the cell volume of the intima increases, there is vascular remodeling so that the lumen is only partially occluded, substantially lessening clinical events resulting from occlusion.

Low-Density Lipoprotein (LDL) in Atherosclerosis and Heart Disease

The stable plaque contains a generous fibrous cap composed of layers of smooth muscle cells ensconced in a substantial extracellular matrix network of collagen, proteoglycans, and elastin. The thick fibrous cap of the stable plaque provides an effective barrier preventing plaque rupture and exposure of lesion prothrombotic factors to blood, thereby limiting thrombus formation and clinical events.

Maintenance of a thick fibrous cap is enabled by regulation of the inflammatory status of the foam cell core of the lesion.

cholesterol and relationship to plaque formation

Thus, stable plaques have small necrotic cores containing macrophage debris and extracellular lipid resulting from secondary necrosis of noninternalized apoptotic macrophage foam cells. Vulnerable Plaque Formation and Rupture The advanced atherosclerotic lesion is essentially a nonresolving inflammatory condition leading to formation of the vulnerable plaque, increasing the risk of plaque rupture.

The vulnerable plaque is characterized by two fundamental morphological changes: Sections of the atheroma with a deteriorated fibrous cap are subject to rupture Figures 4 and 5 A recent lipidomics study showed that stable versus unstable plaques have different lipid subspecies profiles Compared to plasma and control arteries, stable plaques have increased CE containing polyunsaturated fatty acids, which have increased susceptibility to oxidation.

The CE containing polyunsaturated fatty acids are decreased in unstable plaques compared to stable plaques of the same subjects Plaque rupture leads to acute exposure of procoagulant and prothrombotic factors from the necrotic core of the lesion to platelets and procoagulant factors in the lumen, thereby causing thrombus formation Figure 5 Thrombus formation at sites of plaque rupture accounts for the majority of clinical events with acute occlusive lumenal thrombosis causing myocardial infarction, unstable angina, sudden cardiac death, and stroke, Macrophage Cell Death and Efferocytosis Influence Plaque Stability The necrotic core results from a combination of accelerated macrophage death and impaired efferocytosis phagocytosis of apoptotic cells Figure 5 Multiple triggers likely occur in lesions to accelerate macrophage death, including oxidative stress, death receptor activation, and nutrient deprivation Prolonged ER stress and activation of the unfolded protein response UPR contribute to macrophage apoptosis as substantiated by studies showing that apoptosis and the UPR effector, CHOP, increase with each stage of atherosclerosis in humans, but the largest increase is observed in the vulnerable plaque In diabetes and obesity, accelerated formation of an enlarged necrotic core is likely instigated by defective macrophage insulin signaling and saturated fatty acids,which are potent inducers of ER stress.

In addition, other triggers act in tandem with ER stress to accelerate apoptosis. Importantly, HDL can prevent efferocyte apoptosis via ER stress by its cholesterol efflux and anti-oxidant functions, Accelerated apoptotic macrophage death is not sufficient to promote necrosis. Apoptotic cells undergo secondary necrotic death if they are not internalized by phagocyte efferocytosis receptors. Necrotic death leads to the leakage of intracellular oxidative and inflammatory components, which then propagate more inflammation, oxidative stress, and death in neighboring cells Figure 5 The presence of necrotic tissue together with apoptosis is consistent with defective efferocytosis in human plaques.

Studies have shown that the majority of apoptotic cells are free in advanced human lesions, whereas in tonsils apoptotic cells are macrophage-associated These receptors recognize apoptotic cell ligands such as phosphatidylserine, and efferocytosis efficiency is enhanced by bridging molecules such as apoE and MFG-E Compared to apoE3, apoE4 is defective at facilitating efferocytosis of apoptotic cells Components of the necrotic core promote thinning of the fibrous cap.

Loss of extracellular matrix is in part due to death of fibrous cap smooth muscle cells, resulting from macrophage-derived Fas receptor ligand, inflammatory cytokines, and The necrotic core results from a combination of accelerated macrophage death and impaired efferocytosis phagocytosis of apoptotic cells Figure 5 Loss of extracellular matrix is in part due to death of fibrous cap smooth muscle cells, resulting from macrophage-derived Fas receptor ligand, inflammatory cytokines, and oxidation products Figure 5 Smooth muscle cells are inefficient at efferocytosis relying on macrophages to internalize apoptotic smooth muscle cells.

As such, the impaired efferocytosis by lesional Figure 5 Formation of the vulnerable plaque. The vulnerable plaque results from a heightened, unresolved inflammatory status of the lesion foam cell core. Antigen-specific activation of T helper 1 Th-1 cells produces interferong IFNg resulting in a proinflammatory macrophage phenotype. The proinflammatory macrophage foam cells exhibit enhanced inflammatory cytokine secretion and apoptosis susceptibility.

In addition, proinflammatory macrophages have impaired atheroprotective functions including cholesterol efflux and efferocytosis. The defective efferocytosis of inflammatory apoptotic macrophages results in secondary necrosis leading to an enlarged necrotic core composed of leaked oxidative and inflammatory components. This unresolved inflammation causes thinning of the fibrous cap resulting from increased smooth muscle cell death, enhanced extracellular matrix degradation and decreased extracellular matrix production.

Areas of thin fibrous cap are prone to rupture exposing prothrombotic components to platelets and procoagulation factors leading to thrombus formation and clinical events. The extracelluar matrix components are degraded by macrophage-derived matrix metalloproteinases, elastases, and cathepsins Figure 5 Once plaque rupture occurs, critical HDL functions may also include prevention of platelet activation and thrombus formation. Summary Atherosclerotic lesions initiate with endothelial cell dysfunction causing modification of apoB containing lipoproteins LDL, VLDL, remnants and infiltration of immune cells, particularly monocytes, into the subendothelial space Figure 1.

The macrophages internalize the retained apoB containing lipoproteins to become foam cells forming the fatty streak Figure 1. HDL, apoA-I, and endogenous apoE reduce lesion formation by preventing endothelial cell activation, inflammation, and oxidative stress and also by promoting cholesterol efflux from foam cells. As the lesion progresses to fibrotic plaques as a result of continued inflammation, macrophage chemoattractants stimulate infiltration and proliferation of smooth muscle cells Figure 3.

Atherosclerosis | American Heart Association

Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets Figure 4. Unresolved inflammation results in formation of vulnerable plaques, which have large necrotic cores and a thinning fibrous cap Figure 5. Enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells results in necrotic cell death causing heightened inflammation 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 cardiovascular events Figure 5.

ApoB is produced mainly by the liver, where it is required for the synthesis and secretion of triglyceride-rich very low-density lipoprotein VLDL particles Figure 6. In humans, apoB48 is produced exclusively in the intestine through an unique RNA editing mechanism by the apobec-1 enzyme complex ApoB48 is required for the synthesis and secretion of triglyceride-rich chyolmicrons Figure 9which play a critical role in the intestinal absorption of dietary fats and fat-soluble vitamins.

At the most basic level, oxidation is the loss of electrons. When a compound is oxidized, its properties change. For example, unoxidized iron is a strong structurally sound metal, while oxidized iron, because of the loss of electrons, is a brittle reddish powder.

Each LDL particle contains approximately molecules of phospholipids, molecules of free cholesterol, molecules of cholesterol esters, molecules of triglycerides, and one molecule of apoB. Both the protein and lipid moieties can undergo oxidative modification which is a very complex biochemical process.

Recent findings suggest that oxLDL begins to deposit in human coronary arteries before plaque formation and increasingly deposits with plaque growth OxLDL particles may promote atherosclerosis through several mechanisms.

The discovery that vascular wall cells themselves can produce cytokines provided an important insight into the initiation of atherosclerosis. Leukocyte recruitment to the arterial wall is an important initial step in the formation of atherosclerotic lesions.

cholesterol and relationship to plaque formation

The circulating leukocytes that enter the vessel wall are called monocytes but within tissues, they are termed macrophages. Typically, the endothelium resists adhesion of leukocytes derived from blood. However, when stimulated by pro-inflammatory cytokines, adhesion molecules on the surface of endothelial cells may capture leukocytes Cytokines may play a key role in recruiting inflammatory cells in the vascular wall.

Failure of counter-regulatory mechanisms may also promote inflammation and oxidation in atherosclerosis. For example, HDL particles may function as carriers for anti-inflammatory and anti-oxidant mediators HDL is an effective antioxidant.

After reaching the intima, leukocytes macrophages take up modified lipoproteins. These-lipid laden white blood cells are called foam cells.

Foam cells comprise the bulk of early atherosclerotic lesions often termed fatty streaks Foam cells play a critical role in the occurrence and development of atherosclerosis. The Vulnerable Plaque Rupture of the plaque surface, often with blood clotting thrombosis superimposed, frequently occurs during the evolution of coronary atherosclerotic lesions. It is probably the most important mechanism underlying the sudden, rapid plaque progression responsible for acute coronary syndromes Plaque rupture is an important mechanism underlying most cases of acute heart attack and sudden cardiac death.

The concept of plaque rupture was first reported at the autopsy of the celebrated neoclassical Danish artist Bertel Thorvaldsen, who died of sudden cardiac death in the Royal Theater in Copenhagen in Increased permeability of the endothelium and increased retention of LDL particles within the intima are important underlying mechanisms. LDL particles may undergo chemical modification within the intima and become oxidized.

  • Atherosclerosis and cholesterol
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Immune reactions and low-grade inflammation play a crucial role in the formation and progression of atherosclerotic plaques. Rupture of the plaque surface, often with blood clotting thrombosis superimposed, frequently occurs during the evolution of coronary atherosclerotic lesions. Plaques that are prone to rupture are termed vulnerable plaques.

Both curves are bell shaped with the top of the bell corresponding to the medium cholesterol level in each group. The American Journal of Cardiology, The measure accounts for the total amount of cholesterol carried by LDL particles.

So, of course, high blood cholesterol is not enough to cause atherosclerosis.