Current Concept And Machanisms In The Pathogenesis Of Atherosclerosis Essay Example

Current Concept And Machanisms In The Pathogenesis Of Atherosclerosis Paper Atherosclerosis is the leading cause of death and disability in the developed world. Despite our familiarity with the disease, some of its fundamental characteristics remain poorly recognized and understood. Although many generalized or systemic risk factors predispose to its development, atherosclerosis affects various regions of the circulation preferentially and yields distinct clinical manifestations depending on the particular circulatory bed affected. Atherosclerosis of the coronary arteries commonly causes myocardial infarction and angina pectoris. Atherosclerosis of the arteries supplying the central nervous system frequently provokes strokes and transient cerebral ischemia. In the peripheral circulation, atherosclerosis causes intermittent claudication and gangrene and can jeopardize limb viability. Involvement of the splanchnic circulation can cause mesenteric ischemia. Atherosclerosis can affect the kidneys either directly (e. g. , renal artery stenosis) or as a frequent site of atheroembolic disease. Even with in a given arterial bed, atherosclerosis tends to occur focally, typically in certain predisposed regions. In the coronary circulation, for example, the proximal left anterior descending coronary artery exhibits a particular predilection for developing atherosclerotic occlusive disease. Likewise atherosclerosis preferentially affects the proximal portions of the renal arteries and in the extracranial circulation to the brain, the carotid bifurcation. We will write a custom essay sample on Current Concept And Machanisms In The Pathogenesis Of Atherosclerosis specifically for you for only $16.38 $13.9/page Order now We will write a custom essay sample on Current Concept And Machanisms In The Pathogenesis Of Atherosclerosis specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will write a custom essay sample on Current Concept And Machanisms In The Pathogenesis Of Atherosclerosis specifically for you FOR ONLY $16.38 $13.9/page Hire Writer Indeed, atherosclerosis lesions often form at branching points of arteries, regions of disturbed blood flow. Not all manifestations of atherosclerosis result from stenotic, occlusive disease. Ectasia and development of aneurismal disease, for example, frequently occur in the aorta. The mechanisms that underlie this discontinuous anatomic distribution of atherosclerosis remain uncertain. (Rodney A. White, White A. , Ramadan Shaafi, White A. White, 1989) Atherosclerosis manifests itself focally not only in space, as just described, but in time as well. Atherogenesis in humans typically occurs over a period of many years, usually many decades. Growth of atherosclerotic plaques probably does not occur in a smooth linear fashion, but rather discontinuously, with periods of relative quiescence punctuated by periods of rapid evolution. After a generally prolonged silent period, atherosclerosis may become clinically manifest. The clinical expressions of atherosclerosis may be chronic, as in the development of stable, effort-induced angina pectoris or of predictable and reproducible intermittent claudication. Alternatively, a much more dramatic acute clinical event such as myocardial infarction, a cerebrovascular accident, or sudden cardiac death may first herald the presence of atherosclerosis. Other individuals may never experience clinical manifestations of arterial disease despite the presence of widespread atherosclerosis demonstrated post mortem. INITIATION OF ATHEROSCLEROSIS FATTY STREAK FORMATION An integrated view of experimental results in animal and study of human atherosclerosis suggests that the fatty streak represents the initial lesion of atherosclerosis. The formation of these early lesions of atherosclerosis most often seems to arise from focal increases in the content of lipo-protein within regions of the intima. These accumulations of lipoprotein particles may not result simply from an increased permeability or leakiness of the over lining endothelium. Rather this lipoprotein may collect in the intima of arteries because they bind to constituent of the extracellular matrix, increasing the residence time of the lipid- rich particles within the arterial wall. Lipoproteins that accumulate in the extra cellular space of the intima of arteries often associate with proteoglycan molecules of the arterial extracellular matrix, an interaction that may promote the retention of lipoproteins by binding them and slowing their egress from the intima. (James S. C. Gilchrist, Paramjit S. (EDT) Tappia, Thomas (EDT) Netticadan, 2003) Lipoprotein particles in the extracellular space of the intima particularly those born to matrix macromolecules, may undergo chemical modification. Accumulating evidence supports a pathogenic role for such modifications of lipoproteins in atherogenesis. Two types of such alterations in lipoproteins bear particular interest in the context of understanding how risk factors actually promote atherogenesis: oxidation and nonenzymatic glycation. Lipoprotein Oxidation Lipoprotein sequested from plasma antioxidants in the extracellular space of the intima become susceptible to oxidative modification. Oxidatively modified low density lipoprotein (LDL), rather than being defined homogerous entity, actually comprises a variable and incompletely defined mixture. Both the lipid and protein moieties of these particles cab participate in oxidative modification. Modifications of the lipids may include formation of hydroperoxides, lysophospholipids, oxysterols, and aldehydic breakdown products of fatty acids. Modifications of the apoprotein moieties may include breaks in the peptide backbone as well as derivatization of certain amino acid residues. A more recently recognized modification may result from local hypochlorous acid production by inflammatory cells within the plaques, giving rise to chlorinated species such as chlorotyrosyl moieties. Considerable evidence supports the presence of such oxidation products in atherosclerotic lesions. Nonenzymatic Glycation In diabetic patients with sustained hyperglycemia, nonenzymatic glycation of apolipoproteins and other arterial proteins likely occurs that may alter their function and propensity to accelerate atherogenesis. A good deal of experimental work suggests that both oxidatively modified and glycated lipoproteins or their constituents can contribute to many of the subsequent cellular events of lesion development. LEUKOCYTE RECRUITMENT After the accumulation of extracellular lipids, recruitment of leukocyte occurs as a second step in the formation of the fatty streak. The white blood cells types typically found in the evolving atheroma include primarily cells of the mononuclear lineage; monocytes and lymphocytes. A number of adhesion molecules or receptor for leukocyte expressed on the surface of the arterial endothelial cell likely participitate in the recruitment of leukocyte to the nascent fatty streak. Constituent of oxidatively modified LDL can augment expression of leukocyte adhesion molecule. This example of illustrate how the accumulation of lipoprotein in the arterial intima may link mechanistically with leukocyte recruitment and subsequent events in the lesion formation. (Pierre-Jean Touboul, J. R. Crouse, 1997) Laminar shear forces such as those encountered in most regions of normal artery can also suppress of the expression of leukocyte adhesion, example branch points often have disturbed laminar flow. Ordered laminar shear of normal blood flow augments the production of nitric oxide by endothelial cells. This molecule in addition to its vasodilator properties can act at the low levels constitutively produced by arterial endothelium as a local anti-inflammatory autacoid, for example limiting local adhesion molecule expression. These examples indicate how hemodynamic forces may influence the cellular that underlie atherosclerotic lesion initiation and provide a potential explanation for the local distribution of atherosclerotic lesions at certain sites predetermined by altered flow pattern. Once adherent to the surface of the surface of the arterial endothelial cell via interaction with adhesion receptors, the monocytes and lymphocytes penetrates the endothelial layer and take out residence in the intima in addition to products of modified lipoprotein, cytokines can regulate the expression of adhesion molecules involved in the leukocyte recruitment. For example, the cytokines interlukin one (IL-1) or tumor necrosis factor alpha (TNF-alpha) induce or augment the expression of leukocyte adhesion molecules on endothelial cells. Because modified lipoprotein can induce cytokines release from vascular wall cells, this pathway may provide an additional link between accumulation and modification of lipoprotein and leukocyte recruitment. The directed migration of leukocyte into the arterial wall may also result from the action of modified lipoprotein. For example, oxidized LDL may promote the chemotaxis of leukocyte. Also, oxidatively modified lipoprotein can elicit the production by vascular wall cells of chemoattractant cytokines such as monocytes chemoattractant protein-1. (Frank Kessel, Patricia L. Rosenfield, Norman B. Anderson, 2003) FOAM CELL FORMATION Once resident within the intima the mononuclear phagocyte differentiate into macrophages and transform into lipid-laden foam cells. The conversion of mononuclear phagocytes into foam cells requires the uptake of lipoprotein particles by receptomediated endocytosis. One might suppose that the well recognized classical receptor for LDL mediated the lipid uptake. Patients or animals lacking effective LDL receptors due to genetic alterations however have abundant arterial lesions and extraarterial xanthomata rich in macrophage derived foam cells. Also the exogenous cholesterol suppresses expression of the LDL receptor, such that under hypercholesterolemic conditions the level of this cell surface receptor for LDL decreased. Candidates for alternative receptors that can mediate lipid-loading of foam cells include a growing number of macrophage scavenger receptors, which preferentially endocytose modified lipoproteins and other receptors for oxidized LDL or beta-VLDL (very low density lipoprotein) a type of lipoprotein commonly encountered in certain hypercholerterolemic states. By ingesting lipids from the extracellular space the mononuclear phagocytes bearing such scavenger receptors may remove lipoproteins from the developing lesion. Some lipid loaded macrophages may leave the artery wall, functioning to clear lipid from the artery. Lipid accumulation and hence propensity to form atheroma, ensues if the amount of lipid entering the artery wall exceeds that exported by mononuclear phagocytes or other pathways. Macrophages may thus play a vital role in the dynamic economy of lipid accumulation in the arterial wall during atherogenesis. Some lipid laden foam cells within the expanding intimal lesion perish. Some foam cells may die as a result of programmed cell death known as apoptosis. This death of mononuclear phagocytes results in formation of the lipid rich center often called necrotic core, of more complicated atherosclerotic plaques. (Shari R. Waldstein, Merrill E Elias, 2001) Macrophages taking up modified lipoproteins much like intrinsic vascular wall cells may elaborate cytokines and growth factors that can further signal some of the cellular events in lesion complication. A number of growth factors or cytokines elaborated by mononuclear phagocytes can stimulate smooth-muscle cell proliferation and production of extracellular matrix, which accumulates in atherosclerotic plaques. Cytokines found in the plaque including IL-1 or TNF – alpha can induce local production of growth factors such as forms of platelet derived growth factor (PDGF), fibroblast growth factor and others that may contribute to plaque evolution and complication. Other cytokines, notably interferon gamma (IFN-gamma) derived from activated T cells within lesions can inhibit smooth muscle proliferation and synthesis of interstitial forms of collagen. These examples illustrate how atherogenesis likely depends on a complex balance between mediators that can promote lesion formation and other pathways that can mitigate the atherogenic process. (Aron Wolfe Siegman, Timothy W. Smith, 1994) FACTORS THAT MODULATE INHIBITATION OF ATHEROMA Elaboration of small molecules by activated mononuclear phagocytes and vascular wall cells in the evolving lesion may also modulate atherogenesis. Notably reactive oxygen species can modulate growth of smooth muscle cells, activate inflammatory gene expression via the nuclear factor kappa beta (NFk beta) transcriptional control system and annihilate NO radicals, decreasing the effect of this endogenous vasodilator. However macrophage in the lesion may be activated to express the inducible form of the enzyme that can synthesize NO, known as inducible NO synthase. This high capacity form of the enzyme can produce relatively large, potentially cytotoxic amounts of No radicals. While at the low concentrations of NO produced by the constitutive NO synthase in endothelial cells, this radical may produce beneficial effects; when overproduced by activated phagocytes, however it may prove deleterious. Export by phagocytes may constitute one response to local lipid overload in the evolving lesion. Another mechanism, reverse cholesterol transport mediated by high density lipoproteins (HDL), may provide an independent pathway for lipid removal from atheroma. This transfer of cholesterol from the cell to HDL particle involves specialized cell surface molecules such as the ATP binding cassette transporter (ABCA1) (the gene mutated in tangier disease, a condition characterized by very low HDL levels) and a family of scavenger receptors (the B family). Such reverse cholesterol transport explains part of HDL’s antiatherogenic action. (Richard O. Cannon, Julio A. Panza, 1999) Although clear evidence supports lipoprotein disorder as predisposing factors for atheroma formation, other etiologies may contribute to or modulate atherogenesis. For example hypertension constitutes an independent risk factor for coronary events. Male gender and the postmenopausal state also augment the risk of developing coronary artery disease. Premenopausal women have increased HDL levels compared to age matched men. However a favorable lipoprotein pattern only partially accounts for the protection against atherosclerosis conferred by the premenopausal state. Although laboratory studies suggest that estrogens have direct beneficial effects on the arterial wall, clinical trials have not shown that estrogen replacement therapy prevents recurrent myocardial infarction in postmenopausal women. Indeed treatment with a combination of estrogen and progesterone appears to augment cardiovascular events in women with or without prior myocardial infarction. (Susan Wilansky, James T. Willerson, 2002) Diabetes mellitus aggravates atherogenesis. In addition to the well known microvascular complications of diabetes, macrovascular disease such as atherosclerosis causes a great deal of excess mortality in the diabetic population. Diabetes associated dyslipidemias strongly promote atherogenesis. In particular the constellation of insulin resistance, high triglycerides and low HDL often in association with the central adiposity and hypertension frequently seen in type 2 diabetic patients, seems to accelerate atherogenesis potently. As noted above hyperglycemia may promote the nonenzymatic glycation of LDL, LDL modified in this manner, like oxidatively modified LDL, may signal many of the initial events in atherogenesis. Triglyceriderich lipoprotein particles often elevated in poorly controlled diabetic patients also accentuate atherogenesis. Lp(a) (often pronounced lipoprotein little a to distinguish it from apolipoprotein AI and others found in HDL) provides a potential link between hemostasis and blood lipids. The Lp(a) particle consists of an apoprotein (a) molecule bound by a sulfhydryl link to the apolipoprotein B moiety of an LDL particle. Apoprotein (a) has homology with plasminogen and may inhibit fibrinolysis by competing with plasminogen. Other risk factors for atherosclerosis related to blood clotting include elevated levels of fibrinogen or of the inhibitor of fibrinolysis, plasminogen – activator inhibitor 1 (PAI-1). Another nonlipid risk factor for coronary events, elevated levels of homocysteine, may act by promoting thrombosis, although the pathophysiology of this association is uncertain at present. Although individuals with marked elevations of Lp(a) or homocysteine do appear to have heightened risk of coronary thrombosis, in the population at large these factors show a much weaker correlation with vascular events than LDL, HDL, or the global inflammatory marker C-reactive protein (CRP). (Philip M. McCabe, Neil Schneiderman, Tiffany Field, A. Rodney Wellens, 2002) The relationship between tobacco use and atherosclerosis also remains poorly understood. The rapid reduction in risk for cardiac events after cessation of cigarette smoking implies that tobacco may promote thrombosis or some other determinant of plaque stability as well as contribute to the evolution of the atherosclerotic lesion itself. For example tobacco smokers have elevated fibrinogen levels a variable associated with increased atherosclerosis and acute cardiovascular events. INFLAMMATION In other situations, antecedent inflammatory states may predispose toward atherosclerosis. For example Kawasaki disease in childhood may promote developments of vascular lesions in the arteries of adults. Infectious agents continue to be proposed as instigators or potentiators of atherogenesis. However in humans atherogenic role for vital or microbial pathogens remains speculative. In some patients immune or autoimmune reactions may contribute to atherogenesis. In the particular example of the accelerated form of coronary arteriopathy that plagues heart transplant recipients, immunologic factors may contribute importantly to the pathogenesis. (James Shepherd, Sheperd and Gaw, Allan Gaw, 2001) Known monogenic defects in lipoprotein metabolism account for only a fraction of the familial risk for coronary artery disease. Thus other as yet undefined and perhaps multiple genetic factors may contribute to coronary risk. Mechanisms of disease susceptibility involving the arterial wall might account for some of the genetic predisposition to atherosclerosis unexplained by lipoprotein disorders. Application of molecular genetic techniques may identify new polymorphisms linked to coronary risk and may eventually shed light on new pathophysiologic mechanisms. For example some data suggest a link between certain alleles of the genes encoding angiotensin converting enzyme, the cytokine lymphotoxin, or PAI-1 with increased risk of myocardial infarction. Application of genomic technologies may aid identification of modifier genes that modulate individual responses to established risk factors. Large studies currently in progress should clarify these and other potential genetic factors that influence atherosclerosis. REFERENCES: Aron Wolfe Siegman, Timothy W. Smith, 1994. Anger, Hostility, and the Heart; Lawrence Erlbaum Associates Frank Kessel, Patricia L. Rosenfield, Norman B. Anderson, 2003. Expanding the Boundaries of Health and Social Science: Case Studies in Interdisciplinary Innovation; Oxford University Press James Shepherd, Sheperd and Gaw, Allan Gaw, 2001. Lipids and Atherosclerosis; Taylor Francis James S. C. Gilchrist, Paramjit S. (EDT) Tappia, Thomas (EDT) Netticadan, 2003. Biochemistry of Diabetes and Atherosclerosis; Springer Philip M. McCabe, Neil Schneiderman, Tiffany Field, A. Rodney Wellens, 2002. Stress, Coping, and Cardiovascular Disease; Lawrence Erlbaum Associates Pierre-Jean Touboul, J. R. Crouse, 1997. Intima-Media Thickness and Atherosclerosis: Predicting the Risk? ; Taylor Francis Richard O. Cannon, Julio A. Panza, 1999. Endothelium, Nitric Oxide, and Atherosclerosis: From Basic Mechanisms to Clinical Implications; Blackwell Publishing Rodney A. White, White A. , Ramadan Shaafi, White A. White, 1989. Atherosclerosis and Arteriosclerosis: human pathology and experimental animal methods and models; CRC Press Shari R. Waldstein, Merrill E Elias, 2001. Neuropsychology of Cardiovascular Disease; Lawrence Erlbaum Associates Susan Wilansky, James T. Willerson, 2002. Heart Disease in Women; Churchill Livingstone