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 muscle 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. As the underlying cause of heart attack, stroke, and peripheral vascular disease, atherosclerosis is the major cause of death and morbidity in the United States and the industrial world 1.
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 atherosclerosis 2. 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 has led to tremendous progress in our understanding of the pathogenesis of atherosclerosis 3. First, we provide brief description of the cellular and molecular events in the key stages of atherosclerosis.
The endothelial lining of arteries responds to mechanical and molecular stimuli to regulate tone, 4 hemostasis, 5 and inflammation 6 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. These mechanical stimuli activate signaling pathways leading to a dysfunctional endothelium lining that is barrier compromised, prothrombotic, and proinflammatory 9.
In atherosclerosis susceptible regions, the endothelial cells have cuboidal morphology, a thin glycocalyx layer, and a disordered alignment 8 , 10 , In addition, these regions have increased endothelial cell senescence and apoptosis as evidenced by ER stress markers 12 - 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 survival 12 , 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 1 , leading 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 species 25 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 27 - In contrast, an atheroprotective function of HDL is to prevent endothelial activation and enhance NO production to maintain barrier integrity see details below 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, enzymatic , which, 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.
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 33 - Ly6 hi monocytes, versus Ly6 lo , preferentially migrate into the subendothelial space to convert to proinflammatory macrophages in mice 36 - The enhanced migration of Ly6 hi versus Ly6 lo monocytes likely results from increased expression of functional P-selectin glycoprotein ligand-1 In addition, the number of blood monocytes originating from the bone marrow and spleen, especially Ly6 hi cells, increases in response to hypercholesterolemia Furthermore, hypercholesterolemia and atherosclerosis increase monocytosis in humans 40 , During the initial fatty streak phase of atherosclerosis Figure 1 , the 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:cholesterol acyltransferase ACAT , and the resulting cholesteryl ester CE is packaged into cytoplasmic lipid droplets, which are characteristic of foam cells 42 Figure 2 44 , 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 46 , Enzyme-mediated aggregation of apoB lipoproteins enhances uptake via phagocytosis Figure 2 48 , Uptake of native LDL by fluid phase pinocytosis may also contribute to foam cell formation Figure 2 52 , Macrophage Cholesterol Metabolism.
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. 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 receptors 54 , 55 , In addition, plasma membrane cholesterol in macrophage foam cells enhances signaling via inflammatory receptors 61 , 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 lipase 73 , 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 efflux 31 , 75 see details below.
MiRa and MiRb promote atherosclerosis by impairing cholesterol efflux and promoting inflammatory M1 macrophage conversion 78 - Other microRNAs including MiR and MiR exhibit atheroprotective effects by increasing cholesterol efflux and conversion to the anti-inflammatory M2 macrophage phenotype 76 , 81 - HDL carry small non-coding RNAs 77 , which can also reduce or promote atherosclerosis development depending upon composition of individual non-coding RNAs see details below. Although macrophages are the main infiltrating cells, other cells contribute to the development of lesions including dendritic cells 84 , 85 , mast cells, T cells, and B cells Figure 1 86 , Dendritic cells promote the priming of reactive T cell clones and secrete cytokines, functioning in a largely pro-inflammatory capacity They also take up lipid, which leads to inflammasome activation and increased pro-inflammatory cytokine secretion Atherosclerotic plaques also contain a significant number of adaptive immune cells, including T and B lymphocytes.
However, their specific role in atherosclerosis has not yet been elucidated As atherosclerosis progresses, T effector cell numbers increase or remain constant, while T-reg numbers decline.
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- Lipids And Atherosclerosis Annual 2003.
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This reduction in T-regs is due in part to their heightened susceptibility to cell death as well as their impaired trafficking into lesions Further, T-regs may appear fewer in number because they undergo phenotypic switching into other T-reg subtypes. B cells preferentially reside in the adventitial layer of arteries neighboring sites of plaque, in regions known as tertiary lymphoid organs TLOs. The function of B lymphocytes is also subset dependent, with B-1 cells being atheroprotective and B-2 cells being atherogenic.
B-1 cells undergo limited or no affinity maturation and produce natural antibodies NAbs that have broad specificity and low binding affinity. Mice engineered to overexpress a single-chain variable fragment of E06, an IgM NAb directed against oxidized phospholipids oxPL , were found to have reduced atherosclerosis and features consistent with greater overall plaque stability, confirming the atheroprotective nature of these B-1 cell-derived antibodies IgG forms immune complexes with oxLDL and promotes an inflammatory macrophage phenotype while IgE also stimulates macrophages and mast cells to produce proatherogenic cytokines In addition to apoA-I and HDL, the endogenous production of apoE by macrophages is critical in preventing atherosclerotic lesion formation.
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 97 , 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 , - 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 HDL , , 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, C , apoE4 R, R are impaired in stimulating cholesterol efflux - and in preventing inflammation and oxidation , , Consistent with the compromised function of apoE4, human carriers exhibit increased risk of CAD compared to humans expressing apoE3 or apoE2 heterozygous , , 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 In addition, HDL maintains plaque stability by inhibiting degradation of the fibrous cap extracellular matrix through its anti-elastase activity 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 ABCA1 , 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 multifactorial 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 4 , thereby decreasing occlusion and the appearance of clinical symptoms for much of the life of the lesion - 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. 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. 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. In addition, T-reg cells inhibit antigen-specific activation of T helper 1 Th-1 cell to produce interferon gamma IFNg. Thus, stable plaques have small necrotic cores containing macrophage debris and extracellular lipid resulting from secondary necrosis of noninternalized apoptotic macrophage foam cells.
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: 1 Formation of a necrotic core and 2 Thinning of the fibrous cap. 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 In addition, containing lysophosphatidylcholine is increased in unstable plaques indicating enhanced oxidation 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 luminal thrombosis causing myocardial infarction, unstable angina, sudden cardiac death, and stroke , 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 interferon gamma 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 necrotic core results from a combination of accelerated macrophage death and impaired efferocytosis receptor-mediated phagocytosis of apoptotic cells Figure 5 , As apoptotic cells accumulate and fail to be internalized by phagocytes, they undergo secondary necrotic death leading to the leakage of intracellular oxidative and inflammatory components, which then propagate more inflammation, oxidative stress, and death in neighboring 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. 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 Efferocytosis also becomes defective in advanced atherosclerosis through several different mechanisms. These receptors recognize apoptotic cell ligands such as phosphatidylserine , Compared to apoE3, apoE4 is defective at facilitating efferocytosis of apoptotic cells In addition, efferocytosis may be limited by competition for apoptotic cell binding.
For example, oxPLs bind efferocytosis receptors and effectively compete for apoptotic cell recognition. In addition, lesional autoantibodies to oxPL and oxLDL are able to bind to ligands on the apoptotic cell themselves in order to prevent their binding and ingestion. Finally, apoptotic cells in advanced lesions appear to become poor substrates for efferocytosis. 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 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 macrophages likely leads to uncontrolled VSMC death Figure 5. The extracellular matrix components are degraded by macrophage-derived matrix metalloproteinases, - elastases, and cathepsins Figure 5 Importantly, HDL can prevent efferocyte apoptosis via ER stress by its cholesterol efflux and anti-oxidant functions , , Furthermore, HDL drives conversion to the anti-inflammatory M2 macrophages which have enhanced efferocytosis ability compared to inflammatory M1 macrophages 56 , leading to increased plaque stability. Once plaque rupture occurs, critical HDL functions may also include prevention of platelet activation and thrombus formation.
In addition to the role of HDL in stabilizing plaques, recent studies have focused on the lesional loss of specialized proresolving mediators SPM versus proinflammatory factors i. Studies on human atherosclerotic lesions have shown that unstable versus stable plaques have decreased lipid-derived SPM including resolvin D1 and lipoxin A 4 Other lipid derived resolving mediators which impact atherosclerotic plaques include maresin 1 and resolvin D2 Enhancing the lesional IL content also improved atherosclerotic lesion stability In addition, Treg cells likely control atherosclerotic lesion inflammation resolution as recent studies demonstrated that Treg cells regulate efferocytosis in atherosclerotic lesions by secreting IL to stimulate macrophage production of IL to induce Vav-1 activation of Rac1 and increased efferocytosis 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. 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.
An imbalance between inflammatory factors and SPMs is prominent in facilitating formation of the vulnerable plaque. Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic cardiovascular events Figure 5. Apolipoprotein B apoB occurs in two isoforms, apoB and apoB 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 chylomicrons, which play a critical role in the intestinal absorption of dietary fats and fat-soluble vitamins.
Similar to the metabolism of VLDL, chylomicrons are metabolized in the circulation through the hydrolysis of triglycerides by LPL and hepatic lipase to form cholesteryl ester-enriched chylomicron remnants, which release free fatty acids that can be used for energy by the tissues.
Metabolism of ApoB containing lipoproteins. ApoB is critical for the production and secretion of very low-density lipoprotein VLDL by the liver. HDL and lipid-poor apoA-I reduce foam cell formation by stimulating cholesterol efflux. Mutations in the Ldlr gene are the most common cause of familial hypercholesterolemia FH , an autosomal dominant disorder associated with elevated levels of LDL-C and increased risk for premature cardiovascular disease The existence of the remnant receptor pathway was suggested by the fact that patients with homozygous FH, who completely lack LDLR function, have severely elevated levels of LDL-C but normal blood levels of triglycerides.
The clearance of these remnant lipoproteins involves binding to heparin sulfate proteoglycans and the LDLR like protein -1 LRP1 in the hepatic space of Disse, in a process called secretion capture that requires local enrichment by hepatic expression of apoE. Studies by Anitschkow showing that feeding cholesterol in oil to rabbits caused the formation of atheroma, similar to those seen in humans, demonstrated a causal role of cholesterol in the pathogenesis of atherosclerosis in In , Muller described families with inherited high cholesterol and increased risk for cardiovascular disease Yet it would take several decades before compelling evidence from epidemiological studies, such as Framingham and MRFIT , demonstrated that elevated blood cholesterol levels were associated with increased risk of cardiovascular events CVE.
The Seven Countries Studies by Ancel Keys showed that coronary heart disease CHD mortality rates were higher in countries with higher blood levels of cholesterol e. Finland, Norway, and the USA than in countries of southern Europe and Japan with lower blood levels of cholesterol The high levels of cholesterol were proposed to be associated with the amount of saturated fat in the diet. The response to retention hypothesis holds that retention of atherogenic lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis Figure 1.
First articulated in by Williams and Tabas , the hypothesis was based on more than two decades of work demonstrating that apoB-containing lipoproteins are retained in the artery wall by interaction with proteoglycans , Proteoglycans consist of a protein core bound covalently to one or more glycosaminoglycans GAGs. The most common proteoglycans in the artery wall are decorin, biglycan, perlecan, versican, and syndecan-4 There is ionic binding between the positively charged GAGs and negatively charged amino acids of apoB Boren et al.
The major proteoglycan binding site consists of residues in apoB site B , which is in the C-terminal half of apoB Surprisingly, native LDL, despite the strong evidence for its critical role in promoting atherosclerosis, does not induce macrophage foam cell formation or much in the way of inflammation in vitro. These observations led to the hypothesis that LDL has to be modified to promote foam cell formation and induce inflammation.
Binding of proteoglycans induces structural changes in LDL impacting both the configuration of apoB and the lipid composition Hence, the binding of LDL to proteoglycans makes the LDL more susceptible to oxidation and aggregation, which promotes foam cell formation and a proinflammatory response, and the process is self-perpetuating. Furthermore, macrophages express LPL, which can serve as bridging molecules, binding both lipoproteins and proteoglycans , Consistent with an important role for LPL in atherogenesis, the loss of macrophage LPL expression protects mice from atherosclerosis , In addition, macrophages secrete sphingomyelinase, which has been reported to act synergistically with LPL to promote binding of LDL and lipoprotein a Lp a to vascular smooth muscle cells VSMC and the extracellular matrix promoting their retention in the artery , Furthermore, sphingomyelinase induces aggregation and fusion of LDL particles, promoting increased binding to proteoglycans and induces foam cell formation Thus, interfering with the retention of apoB-containing lipoproteins in the artery wall is a potential strategy for preventing atherosclerosis.
The response to retention hypothesis for the initiation of atherosclerosis posits that retention of LDL in the artery wall leads to its modification into highly atherogenic particles that initiate inflammatory responses. Uptake of oxLDL by macrophages leads to marked accumulation of cholesterol, converting them to foam cells and initiating development of atherosclerotic lesions.
In addition to serving as a substrate for cholesterol accumulation, oxLDL exerts a wide range of bioactivities that are consistent with it being critical for driving atherogenesis Table 1. In mouse models, loss of enzymes that modulate LDL oxidation increases atherosclerosis, and dietary antioxidants that reduce levels of oxLDL also inhibit atherosclerosis. Although human trials with dietary antioxidants have failed to reduce disease outcomes, it is important to recognize that these interventions are less efficacious in reducing oxLDL levels in humans than in rodent models.
Additional studies are needed to determine optimal interventions for lowering oxLDL levels and whether such interventions will be effective for preventing or treating atherosclerosis. View in own window. The outer shell of lipoproteins is composed of phospholipids with polyunsaturated fatty acid PUFA side chains. This vulnerability results from the relatively low energy required for free radicals to abstract hydrogen atoms located between two adjacent double bonds bis-allelic hydrogens.
Asian-Pacific Society of Atherosclerosis and Vascular Diseases Congress
Hydrogen abstraction by free radicals creates a lipid radical that reacts nearly instantaneously with any molecular oxygen present in the environment. Secondary products that may be relevant to atherogenesis can be thought of in two broad classes: oxidized lipids primarily oxidized phospholipids but also oxidized cholesterol esters and reactive lipid aldehydes that exert their effects by modifying proteins and other macromolecules.
Reactive lipid species include malondialdehyde , 4-hydroxynonenal , and isolevuglandins that modify proteins associated with lipoprotein particles including ApoB Figure 7. Oxidation of Phospholipid Polyunsaturated Fatty Acids. Oxidation of phospholipids containing polyunsaturated fatty acids present in plasma lipoproteins results in formation of a variety of reactive lipid aldehydes and oxidized phospholipids that convert these lipoproteins to atherogenic particles.
It is critical to keep in mind that oxidatively modified LDLs oxLDLs are in fact highly heterogeneous and complex particles, even though oxLDL is usually referred to as a discrete entity. Oxidation of LDL in vitro has been used extensively to study the biological activities of oxLDL, but, even here, the actual species present varies significantly based on the oxidation method exposure to air, to copper, or to oxidases and length of oxidation.
Many of the methods commonly used to measure the concentration of oxLDL in vivo only measure general characteristics of oxLDL. For instance, because the reaction of reactive lipid species with lysine residues of ApoB converts LDL from a positively charged particle to a negatively charged particle, oxLDL is often detected by increased mobility during agarose gel electrophoresis.
Alternatively, oxLDL in plasma and other tissues can be quantified by the immunoreactivity of the natural IgM autoantibody E However, while E06 recognizes a variety of oxidized phosphatidylcholines, it does not necessarily recognize all oxPL equally. Therefore, equivalent E06 immunoreactivity does not necessarily mean exposure to identical oxLDL particles.
Therefore, it is important to keep in mind that in vivo oxLDL is a mixture of many different compounds and that the atherogenic activities of oxLDL represent the net cellular responses to the full range of compounds present. While oxLDL has been studied in greatest detail, all lipoproteins are vulnerable to oxidation at least in vitro, and this oxidative modification alters their biological activities in ways that may be atherogenic.
The species of plasma lipoprotein that has the highest content of oxidized phospholipids oxPL depends on the species of oxPL under consideration. This suggests that not all oxPL are formed in situ on the lipoprotein where they are found and might instead be transferred from other lipoproteins or tissues. Lp a is the major carrier in plasma of oxPLs that are detected by E06 immunoreactivity and these oxPLs associate with Lp a in preference to native LDL particles in human plasma E06 immunoreactive oxPL generated in chemically oxidized LDL can rapidly transfer to Lp a , so the high content of these lipids in Lp a isolated from human plasma may be due either to direct oxidation of Lp a or by transfer of the oxPL from oxLDL to Lp a.
Because MDA-modified proteins do not readily transfer between particles, these findings suggest that oxidation initially occurs in LDL with subsequent transfer of oxPL to Lp a. Thus, a physiological role has been proposed for Lp a in binding and transporting oxPL in the plasma As with Lp a , the high levels of these oxPLs in HDL may well be the result of transfer from other oxidized lipoproteins and tissues.
Because oxidation is unlikely to occur in the circulation, the rate that oxPL are transferred from tissue to various plasma lipoproteins could potentially be an important determinant of the risk for atherosclerosis. Significant correlations have been found between levels of oxLDL and extent of atherosclerosis in human patients. Measurement of oxLDL using E06 antibody showed that: 1 significant elevation of oxLDL in acute coronary syndromes , 2 treatment with a statin markedly reduced these levels , 3 oxLDL levels are higher in children with familial hypercholesterolemia compared to their siblings , and 4 oxLDL levels predict the presence and progression of atherosclerosis and symptomatic cardiovascular disease Thus, there is a clear correlation between the presence of oxLDL and cardiovascular disease.
The precise mechanisms that generate oxidized lipoproteins in vivo are still only partially understood. LDL circulating in the plasma appears to be protected from oxidation, both by dietary antioxidants such as vitamin E and C and by protective enzymes including glutathione peroxidases , , peroxiredoxins, PAF-acetylhydrolase also known as lipoprotein-PLA2 , , and paraoxonases PON , Penetration of LDL into the artery wall occurs at branch points in the aorta and other places with turbulent flow and shear stress. Retention of LDL in the intima, due to interactions with extracellular matrix such as chondroitin sulfate-rich proteoglycans, sequesters LDL away from the antioxidant environment of the plasma and exposes LDL to oxidation.
A variety of oxidases and peroxidases generate strong oxidants that can readily oxidize LDL. The extent that each of these enzymes contributes to lipoprotein oxidation in vivo and thus to atherosclerosis remains to be fully elucidated, and there is much we do not understand about these individual processes. Increased MPO blood levels also associate with increased risk for atherosclerosis - and polymorphisms in the MPO gene that lower MPO activity reduce the risk for atherosclerosis , Incubation of lipoproteins with MPO generates oxidized phospholipids that serve as ligands for CD36 It also generates reactive lipid dicarbonyls such as isolevuglandins that modify ApoAI and phosphatidylethanolamine In the presence of small molecules that scavenge lipid dicarbonyls, the ability of MPO to crosslink ApoAI is markedly reduced Modification of HDL by lipid dicarbonyls such as isolevuglandins and MDA reduce its ability to drive cholesterol efflux from macrophages and protect against inflammatory stimuli such as LPS , Transplantation of bone marrow from genetically altered mice into atherosclerosis susceptible strains e.
The reasons for these paradoxical findings with both MPO overexpression and deletion remain unclear. Perhaps the complete lack of MPO activity is harmful because it allows overgrowth of specific microbes that incite atherosclerosis via alternative mechanisms. In contrast to effects of complete ablation, a recently developed selective MPO inhibitor e. Thus, clinical studies with selective MPO inhibitors are needed to determine if this will be a meaningful therapeutic approach to the treatment of atherosclerosis in humans.
Although the primary substrates for lipoxygenases are non-esterified fatty acids, exposure of LDL to LOX also leads to oxidation of phospholipids and cholesterol esters , Nevertheless, the role of LOX in human atherogenesis is less clear-cut. While homozygotes of an Alox15 variant that almost completely ablates LOX activity tended to have a reduced risk for coronary artery disease, heterozygotes paradoxically have increased risk of disease Other polymorphisms in the Alox15 gene encoding LOX increase risk for coronary artery calcification , yet others have no effect Direct correlations between Alox15 polymorphisms and biochemical measurements of oxidized lipoproteins or oxPL and oxidized cholesterol esters have not been reported to date in humans, but are clearly needed.
While internalization of LDL by the LDLR in hepatocytes downregulates cholesterol synthesis to maintain cholesterol homeostasis, internalization of oxLDL by scavenger receptors fails to trigger this inhibition , , Thus, cholesterol synthesis continues unabated despite the fact that peripheral cells are accumulating large amounts of cholesterol. In particular, macrophages express scavenger receptors and gluttonously take up large quantities oxLDL to form foam cells in the initial atherosclerotic lesion OxLDL also activates a number of cellular responses in macrophages, dendritic cells, endothelial cells, T cells, and smooth muscle cells that in aggregate promote inflammation, lesion formation, atherogenesis, and unstable atherosclerotic plaques - OxLDL induces surface expression of adhesion molecules and the release of chemokines from endothelial cells - , all of which are important steps in recruitment of leukocytes to sites of lesions.
OxLDL itself also serves as a neo-antigen OxLDL also induces increased antibody generation by lymphocytes OxLDL also promotes smooth muscle cell proliferation, migration, and transition to a proinflammatory phenotype - OxLDL induces secretion by macrophages of inflammatory cytokines e. OxLDL polarizes macrophages towards the M1-like phenotype or M2-like phenotype depending on its extent of oxidation OxLDL promotes the chemotaxis of monocytes, neutrophils, eosinophils, and T cells , - , bringing them into the arterial wall.
In contrast, oxLDL inhibits macrophage emigration out of atherosclerotic lesions, because it induces netrin-1 OxLDL induces apoptosis of macrophages and development of unstable plaques prone to rupture - Thrombotic arterial occlusion in the aftermath of plaque rupture is a critical cause of mortality, therefore the fact that oxLDL increases platelet aggregation - suggests an additional mechanism whereby elevated circulating oxLDL may increase risk of mortality during acute coronary events As discussed in detail below, identification of cognate receptors for various components of oxLDL and other oxidized lipoproteins has provided important insight into the mechanisms by which these oxidized lipoproteins exert their pathophysiological effects.
The Aging Risk and Atherosclerosis: A Fresh Look at Arterial Homeostasis
The lack of feedback inhibition during uptake of modified LDL by this unidentified receptor suggested a plausible mechanism for the massive accumulation of cholesterol in macrophages that generates foam cells. The putative receptor mediating this binding was named the macrophage scavenger receptor MSR.
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In , Kodama et al. These scavenger receptors belong to a larger family of pattern recognition receptors, all of which are individually capable of binding to a wide spectrum of ligands. The specific ligands of the two receptors on oxLDL appear to diverge Recent findings suggest that SR-AI and other scavenger receptors have both pro- and anti-atherosclerotic effects, depending on the context. The complex results of scavenger receptor deletion should not be surprising given that scavenger receptors have multiple ligands and that an important role of scavenger receptors expressed by macrophages is to allow these macrophages to remove bacteria and damaged cells from surrounding tissues.
Under normal physiological conditions, uptake of oxLDL by macrophages is probably generally protective, because subsequent efflux of the cholesterol from the macrophages to HDL via reverse cholesterol transport as well as emigration of these macrophages from the arterial wall to lymph nodes serves to minimize the accumulation of cholesterol-laden macrophages in the arterial wall. However, under conditions where reverse cholesterol transport capacity is reduced or where emigration of macrophages is inhibited, uptake of oxLDL by macrophages leads to its accumulation and initiation of pathophysiological processes.
In addition to scavenger receptors, other pattern recognition receptors also recognize components of oxLDL. Other factors of the innate immune response that bind oxidized phospholipids including C-reactive protein CRP , and natural IgM antibodies like E06 , While scavenger and pattern recognition receptors tend to recognize broad classes of compounds, a number of G-protein coupled receptors GPCRs recognize specific oxidized phospholipids.
These include the receptor for platelet-activating factor PAFR - , prostaglandin receptor EP2 , , and sphingosinephosphate receptor 1 S1P1 Given the susceptibility of LDL to oxidation, it is perhaps not surprising that a number of mechanisms appear to exist in order to protect LDL from oxidation. These include small molecule antioxidants circulating in plasma and enzymes that catabolize oxidized lipids. How essential each of these mechanisms are to the control of oxLDL levels and preventing the development of atherosclerosis remains an area of active investigation.
Obviously, a better understanding of the relationship between changes in protective mechanism and atherogenesis might allow identification of particularly vulnerable individuals and the development of novel therapeutic approaches. Circulating small molecule antioxidants such as ascorbate vitamin C , alpha-tocopherol vitamin E , urate, and bilirubin serve as sacrificial targets reacting with free radicals and reactive oxygen species to prevent lipid and protein oxidation. Thus, even when strong oxidants are added to plasma ex vivo, there is relatively little generation of oxLDL until the oxidants have depleted these small molecule antioxidants, most specifically ascorbate Importantly, plasma ascorbate levels inversely correlate with prevalence of cardiovascular disease in humans Supplementation with vitamin C appears to play a role in preventing endothelial dysfunction in humans However, it is not clear that supplementing dietary antioxidants beyond those typically obtained in a well-balanced diet endows any additional atheroprotective effects.
Supplementation with dietary antioxidants inhibits development of atherosclerosis in susceptible mice - While a few human trials with dietary antioxidants have demonstrated reduced atherosclerosis and cardiovascular disease - , most large-scale trials have failed to demonstrate any disease reduction - The reasons underlying these failures continue to be investigated and debated , Because it had not been fully appreciated that relatively high doses of these antioxidants were needed to markedly alter lipid peroxidation rates in humans , one possibility is that the doses used in most large scale prevention trials were simply insufficient , However, the ability to use very high doses of small molecule antioxidants like vitamin E for extended periods of times may be limited by the toxicity of these high doses Antioxidant enzymes appear to play a more critical role than dietary antioxidants in limiting lipoprotein oxidation.
Two families of nonheme peroxidases, the glutathione peroxidases and the peroxiredoxins, appear to be the most critical. Glutathione peroxidases Gpx are selenoproteins that convert glutathione to glutathione disulfide while reducing peroxides including lipid peroxides to water , Polymorphisms in glutathione peroxidase 1 Gpx1 are associated with increased risk for atherosclerosis in various human populations - Peroxiredoxins Prdx are cysteine containing proteins where the cysteine is oxidized to sulfenic acid during reduction of peroxides In contrast, overexpression of Prdx6 failed to inhibit atherosclerosis in C57BL6 mice fed an atherogenic diet In general, studies looking for associations between risk for atherosclerosis and polymorphisms or deficiencies in other major antioxidant genes including catalase, SOD-1, -2, and -3, and glutathione S-transferase have been negative , In fact, SOD-1 overexpression may even increase fatty streak lesions in mice Several studies have demonstrated an association between SOD2 and hypertriglyceridemia , F2-isoprostane-PC sn-2 chains Whether this effect results in a net gain of pro- or anti-inflammatory lipids is controversial, because only some of these oxPL are highly potent inflammatory mediators, while others are partial agonists that might therefore antagonize inflammatory responses to other mediators like LPS.
Furthermore, this hydrolysis generates lysoPC and lysoPAF, which are proinflammatory at high concentrations.
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