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Pathogenesis of Atherosclerosis


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Pathogenesis of Atherosclerosis

  1. 1. Atherosclerosis Atherosclerosis is characterised by intimal lesions called atheromas that protrude into vessel lumens. An atheromatous plaque consists of a raised lesion with a soft, yellow core of lipid (mainly cholesterol and cholesterol esters) covered by a white fibrous cap. In addition to mechanically obstructing blood flow, atherosclerotic plaques can rupture, leading to catastrophic vessel thrombosis; plaques also weaken the underlying media and thereby lead to aneurysm formation. Key steps of pathogenesis: Endothelial injury, which causes increased vascular permeability, leukocyte adhesion, and thrombosis Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells Platelet adhesion Factor release from activated platelets, macrophages, and vascular wall cells, inducing smooth muscle cell recruitment, either from the media or from circulating precursors Smooth muscle cell proliferation Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cells) The major mechanisms of atherogenesis Endothelial Injury Endothelial loss due to any kind of injury — results in intimal thickening; in the presence of high-lipid diets, typical atheromas ensue. However, early human lesions begin at sites of morphologically intact endothelium. Thus, endothelial dysfunction underlies human atherosclerosis; in this setting, dysfunctional endothelial cells show; • Increased endothelial permeability, • Enhanced leukocyte adhesion • Altered gene expression
  2. 2. The specific pathways and factors contributing to endothelial cell dysfunction in early atherosclerosis are not completely understood, many etiologic culprits are suspected and these can stimulate pro-atherogenic patterns of endothelial cell gene expression. However, the two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia. 1. Hemodynamic Disturbances Plaques tend to occur at Ostia of exiting vessels, branch points, and along the posterior wall of the abdominal aorta, where there are disturbed flow patterns. • Non-turbulent flow in the normal vasculature leads to the induction of endothelial genes whose products protect against atherosclerosis. 2. Lipids Lipids are typically transported in the bloodstream bound to specific apoproteins (forming lipoproteins). Dyslipoproteinemias can result from mutations that alter the apoproteins or the lipoprotein receptors on cells, or from other disorders that affect the circulating levels of lipids. The mechanisms by which hyperlipidemia contributes to atherogenesis include: • Hyperlipidemia can directly impair endothelial cell function by increasing local oxygen free radical production; oxygen free radicals can injure tissues and accelerate nitric oxide decay, reducing its vasodilator activity. • With chronic hyperlipidemia, lipoproteins accumulate within the intima. These lipids are oxidized through the action of oxygen free radicals locally generated by macrophages or endothelial cells. Oxidized LDL is ingested by macrophages through a scavenger receptor, and accumulates in phagocytes, which are then called foam cells. In addition, oxidized LDL stimulates the release of growth factors, cytokines, and chemokines by endothelial cells and macrophages that increase monocyte recruitment into lesions. Finally, oxidized LDL is cytotoxic to endothelial cells and smooth muscle cells and can induce endothelial cell dysfunction.