Update on the pathogenesis of atherosclerosis

Abstract

The major components of atherosclerotic plaque, ultimately responsible for clinical effects, are deposited lipids—mostly cholesteryl esters and cholesterol, derived largely from the lower-density lipoproteins of the blood—and proliferated, modified arterial smooth muscle cells with their synthesized connective tissue products. Advanced plaques vary widely in the proportion of the two components, but evidence indicates that lipid deposition—especially of lipoprotein elements—often occurs in the lesion-prone intimal areas of the artery prior to the buildup of smooth muscle cells. The 1980s were remarkably productive for investigators who study the pathogenesis of atherosclerosis. We now know of the many forms of lower-density lipoproteins, i.e., low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL), some of which are more likely to be associated with accelerated atherosclerosis and some of which are more likely to be influenced by diet. Among these forms of LDL and VLDL are LDL-1, β-VLDL, and Lp(a). Work has been reported implicating various alterations of endothelial function in the permeability of the arterial endothelial barrier in the transport of these low-density, cholesterol-rich macromolecules. Of possibly greater interest is the developing evidence that such proliferation-stimulating molecules as platelet-derived growth factor (PDGF) can be produced by a number of cells likely to be involved in the progression of atherosclerotic plaque. In addition to platelets, these include activated monocytes and monocyte-derived macrophages, injured endothelial cells, and smooth muscle cells, which can undergo an autocrine conversion to PDGF synthesis—possibly stimulated by LDL from hyperlipidemic serum. Leukotrienes and other endothelium-associated regulatory molecules may also take part in the paracrine and autocrine mechanisms of stimulating smooth-muscle-cell proliferation. Additional recent developments that have led to a better understanding of atherosclerotic pathogenesis have occurred. The first is evidence of the involvement of oxidized LDL and its apolipoprotein B in atherogenesis. Research indicates that antioxidants have a suppressive effect on atherogenesis when oxidized LDL has been involved in lesion development. The data linking the development of autoimmune reactions to these oxidatively altered lipoproteins are also impressive. Further, there is increasing evidence that atherogenesis in nonhuman primates and in people in whom chronic sustained circulating immune complexes are involved is likely to be accelerated, even when few or no classic risk factors are present. These lesions appear to represent a distinct microarchitectural form of concentric and transmural atherosclerosis that is better classified as “atheroarteritis.”