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Pathogenesis of Atherosclerosis
Artery diseases are of immense concern to medical researchers due to the cause and effect relationship shared with heart disease and cardiovascular mortality. Atherosclerosis is one of the diseases earning such focus from researchers because of its multifactorial nature, and its period of development which typically occurs years before clinical symptoms are apparent. Atherosclerosis is a disease of the arterial wall that promotes several common causes of cardiovascular mortality, including myocardial infarction and cerebrovascular disease (Channon 2002). The term "atherosclerosis" was traditionally used to describe an abnormality in lipid metabolism, an end-stage degenerative disease, and vessel stiffening. Further studies have caused a rapid increase in knowledge of the pathogenesis of atherosclerosis, and suggest the inciting event of atherosclerosis is more likely an inflammatory event which occurs years before evidence of the disease clinically manifests (Crowther 2005).
Cellular and molecular mechanisms that underlie atherosclerosis demonstrate the roles of the endothelium, inflammation, and smooth muscle cells in plaque biology, and ultimately disease progression that occurs over time. The earliest stages of the atherosclerotic process are marked by endothelial dysfunction. The disease is likely initiated by loss of endothelial nitric oxide bioactivity, the over-expression of adhesions molecules in response to turbulent flow, and inflammatory cascades (Crowther 2005; Channon 2002). Studies also highlight the role of shear stress in regulating the inflammatory processes that initiate and promote the growth of fibroinflammatory lipid plaque (Cunningham 2005). The pathogenesis of atherosclerosis is multifaceted and intricate as it involves a host of cell processes and inflammatory responses. Evolving insights into the pathogenic properties reveal the potential for new treatment methods that will address the disease progression. Understanding atherosclerosis as a disease that develops over time, in opposition to original beliefs about the disease, is critical to defining its pathogenesis.
Atherosclerosis is a disease identified by the build up of plaque within blood vessels as artery walls thicken due to the accumulation of fatty materials. This thickening is induced by an inflammatory response, in which endothelial dysfunction is the primary trigger for atherosclerosis. Atherosclerotic lesions are the results of three key components. The first is the cellular component, and primarily involves smooth muscle cells and macrophages. The second component is the extracellular lipid and the connective tissue matrix. The third component of atherosclerotic lesions is the intracellular lipid that accrues within macrophages, creating foam cells. The three components encompass the lesion, which develops as a result of inflammatory response, consequential release of various cytokines, proliferation of smooth muscle cells, and the amassing of macrophages and lipids (Crowther 2005, p. 436).
A normal, healthy artery is comprised of the endothelium, its basement membrane that lines the lumen, the media layers made of smooth muscle cells, elastin fibers and extracellular matrix, and the surrounding adventitia of connective tissue (Channon 2002, p. 54). The endothelial cell layer is critical for maintaining vascular homeostasis, stimulating physiological transduction, responding to signaling molecules, and mediating the connection between blood in the lumen and the vessel wall. One of the most important signaling molecules produced by the endothelium is nitric oxide (NO), which is generated in normal blood vessels by the endothelial nitric oxide synthase enzyme (eNOS). NO is a reactive free radical, and disperses from endothelial cells into the vessel lumen, smooth muscle cells, activates soluble guanylate cyclase, and consequently causes smooth muscle relaxation and artery dilation (Channon 2002, p. 54). NO networks with a variety of other signaling molecules and pathways, including other cellular enzymes, ion channels and mitochondrial respiration.
The effects of NO on the vessel wall contribute to the early pathogenic process of atherosclerosis. The loss of NO bioactivity in the endothelium is associated with causal complex of thrombosis, inflammatory cell adhesion and recruitment (Channon 2002, p. 54). Endothelial dysfunction and activation caused by loss of NO bioactivity allows for macrophage adhesion and recruitment. The resulting accumulation of macrophages and oxidized lipid causes fatty streaks. Plaque formation occurs as foam cells (lipid-laden macrophages) and necrotic material accumulate in the lipid core. The increased lipid content and macrophage activation in the lipid core result in the secretion of pro-inflammatory cytokines, synthesis of procoagulant molecules, and the production of matrix metalloproteinases that compromise the collagen in the fibrous cap (Channon 2002, p. 57). The lipid core is lined with smooth muscle cells and forms the fibrous cap, and the loss of smooth muscle cells is a consequence of apoptosis and reduced collagen synthesis. Plaque rupture is the result of the fibrous cap rupture as activated macrophages secrete matrix-degrading enzymes.
Once plaque rupture occurs, the exposure of the plaque core and collagen causes platelet adhesion and thrombosis, which allows for rapid plaque expansion and lumen blockage (Channon 2002, p. 56). The loss of endothelial NO bioactivity is the one of the basic characteristics of endothelial dysfunction in vascular diseases, which is related to the levels of eNOS in the endothelium. A deficiency of the eNOS co-factor, tetrahydrobiopetrin, may reduce eNOS activity, and the availability of L-arginine may also limit NO production (Channon 2002, p. 55). The lack of interaction between these molecules and the eNOS enzyme showcase the complexity of endothelial dysfunction and resulting atherosclerosis. The initiation of the atherosclerotic process is also attributed to the over-expression of adhesion molecules in response to turbulent flow in an unfavorable lipid concentration. Increased cellular adhesion and other associated dysfunctional characteristics are conducive for the recruitment of inflammatory cells, the release of cytokines, and the recruitment of lipid into the plaque (Crowther 2005, p. 436).
The pathogenesis of atherosclerosis is no longer understood as a problem with lipid metabolism, but is widely accepted the earliest stages of the atherosclerotic process is mediated by the inflammatory cascade. Atherosclerosis is initiated when the expression of adhesive proteins cause leukocytes to adhere to the endothelium. Vascular cell adhesion molecule-1 (VCAM-1) expression increases the recruitment of T-cells and monocytes to the location of endothelial injury. This induces the release of monocyte chemo-attractant protein-1 (MCP-1), and intensifies the inflammatory cascade by recruiting additional leukocytes, activating leukocytes in the media, and triggers the recruitment and proliferation of smooth muscle cells (Crowther 2005, p. 437). After adhering to the endothelium, leukocytes then cross the endothelial barrier and begin to accumulate. This is conducted in response to signals generated within the early plaque, causing monocytes to adhere to the endothelium. Monocytes then migrate through the endothelium and basement membrane by elaborating enzymes, which ultimately degrade the connective tissue matrix (Crowther 2005, p. 437).
Once monocytes have infiltrated the sub-endothelial space, the development of atherosclerosis is advanced through subsequent cytokine release. Recruited macrophages release additional cytokines, and begin to travel through the endothelial surface and into the media of the vessel. The release of monocytes-colony stimulating factor (M-CSF) further intensifies the migration of the macrophages, and causes monocytic proliferation. The local activation of monocytes induces cytokine-mediated progression of atherosclerosis, in addition to the oxidation of low-density lipoprotein (LDL) (Crowther 2005, p. 437). Once this process is in motion, several mediators of inflammation influence the further development of atherosclerotic plaque. For example, CD40L has been shown to increase the expression of tissue factor in plaques and consequently the probability of thrombosis, and other inflammatory mediators expressed by smooth cells within plaque include: interleukin (IL)-1?, IL-6, IL-18, M-CSF, and tumor necrosis factor (TNF) (Crowther 2005, p. 437). The role of these mediators (and several more which are not listed), represent models for the role of inflammatory elements in the pathogenesis of atherosclerosis.
Atherosclerosis is not clinically apparent until after the cytokine release and following recruitment of macrophages, and there is a noted accumulation of foam cells. The atherosclerotic lesion becomes clinically evident by its characterized intimal narrowing, foam cell accumulation, neovascularization and flow-limiting narrowing. By this stage, the disease is profoundly advanced and ensuing treatments do not influence the pathogenesis of the underlying disorder (Crowther 2005, p. 437). The evolution of the atherosclerotic plaque is illustrated by enlargement of the plaque over time due to the deposit of foam cells. The varying rates of plaque growth leads researchers to question the mechanism of acute thrombotic occlusion in comparison to the mechanism of more slowly growing fibrous plaques (Crowther 2005, p, 438). The enlarging plaque may cause chronic stable angina, myocardial infarction, and a multitude of other cardiac complications.
The role of blood flow-induced shear stress has also emerged as a contributing factor in the pathophysiology of atherosclerosis. Shear stress refers to the fluid drag force acting on the vessel wall, which is induced by a biochemical signal with the ability to affect vascular behavior (Cunningham & Gotlieb 2005, p. 9). Shear stress is a significant factor in regulating the inflammatory processes that initiate and promote the growth of fibroinflammatory lipid plaque. The influence on vascular inflammation caused by shear stress is a result of modification of endothelial gene expression to a proatherogenic profile (Cunningham & Gotlieb 2005, p. 13). Recent studies using microarray analyses comparing conditions of laminar and disturbed shear stress suggest nonlaminar flow can cause gene expression of proinflammatory molecules in the vascular…[continue]
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