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An Overview of Atherosclerosis
Introduction
Arteriosclerosis is a generic term used for describing hardening and thickening of arteries. Atherosclerosis is the most common form and is responsible for several common clinical manifestations such as stroke, coronary artery diseases, peripheral arterial disease, and aortic aneurysm. It is a major contributor to worldwide morbidity and mortality and in the Western world is responsible for more than half the annual mortality. It is postulated that the socioeconomic impact of this disease will continue to increase.
High plasma levels of low-density lipoprotein (LDL) provide sufficient plasma apolipoprotein B-containing lipoproteins that can cause clinical atherosclerosis, such as in familial hypercholesterolemia. Often, however, symptomatic atherosclerosis develops at LDL levels within or close to the normal range of the population, but in combination with other risk factors that facilitate atherosclerosis or its clinical complications. These other factors include smoking, high blood pressure, diabetes, male gender, and a complex genetic susceptibility to the disease.
Cellular and Molecular Mechanisms in Atherosclerosis
Atherosclerosis is a disease in which inflammation has been implicated in every step of the process—from the onset, to the slow progression over years and to the final catastrophic plaque rupture, which typically makes it symptomatic. An array of different cellular players and molecular pathways contribute to different steps in atherogenesis. Endothelial cell dysfunction is a key early step resulting in upregulation of leukocyte adhesion molecules on the surface such as P-selectin, E-selectin, vascular cellular adhesion molecule, and intercellular adhesion molecules. Circulating monocytes start the process of adhesion by upregulating receptors on the endothelial surface. Cytokines such as interleukins (IL-1α and IL-1β) are secreted into the plasma by activated monocytes and macrophages, and play an important role in upregulating leukocyte adhesion molecules on the endothelial cells as well cause proliferation of vascular smooth muscle cells and production of other cytokines. These proinflammatory cytokines, chemokines, and growth factors further elaborate this response in the vessel wall. Other external factors such as hypoxia, reactive oxygen species, and even excess nitric oxide help this process onward.
Monocytes enter the intima by a process of diapedesis. Besides monocytes, various other cells such as neutrophils, T cells, and dendritic cells play important roles in mediating the inflammatory process. Subendothelial lipids are oxidated and are taken up by macrophages to form foam cells. Macrophages and the proinflammatory foam cells are by and large the predominant cell types in the fibrous plaque. As these macrophages and foam cells die, the intracellular contents including lipoproteins and cholesterol crystals are released, leading to formation of the plaque’s necrotic core. Smooth muscle cells migrate from the tunica media into the intima and are a prominent and important feature of the atherosclerotic plaque. They exist in two distinct phenotypes, the contractile or quiescent form, and the proliferative or active form. Smooth muscle cells importantly also synthesize the collagen strands, fibrin, and proteoglycans that make the fibrous cap in response to various cytokines.
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