Peroxisome proliferator–activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor–deficient mice

Abstract

Complications of atherosclerosis are the leading cause of death in Western societies and have an extremely high incidence in individuals with type 2 diabetes mellitus (1, 2). Atherosclerosis is initiated by the accumulation of plasma LDL in the arterial wall, its oxidation, and the recruitment of circulating monocytes Once monocytes in the arterial intima have undergone phenotypic transformation to macrophages, they take up oxidized LDL (oxLDL) via several scavenger receptors that include scavenger receptor A (SR-A), CD36, and macrosialin (5-7). This results in massive cholesterol accumulation and formation of foam cells. Interactions between oxLDL, macrophages, smooth muscle cells infiltrated from the arterial media, and T cells recruited from the circulation result in a chronic inflammatory condition that is thought to influence the further evolution of early atherosclerotic lesions toward more advanced, clinically relevant lesions (8). Interactions between arterial cells are mediated by an array of cytokines and adhesion molecules (9), and increasing experimental evidence suggests that many of these factors promote atherogenesis. For example, hypercholesterolemic mice in which the gene encoding macrophage chemotactic protein 1 (MCP-1) has been disrupted are resistant to the development of atherosclerosis (10, 11). In analogy, disruption of the SR-A and CD36 genes results in a significant reduction of hypercholesterolemia-induced atherosclerosis in mice These observations suggest that interventions directed at altering the genetic responses of vascular cells to proatherogenic stimuli, such as hypercholesterolemia, may be beneficial.