Peroxisome Proliferator Activator Receptor Gamma Agonists Inhibit the Development of Atherosclerosis in Low Density Lipoprotein Receptor-Deficient Male Mice

Abstract

Atherosclerosis is the leading cause of morbidity and mortality in Western societies and is a major complication in patients with Type 2 diabetes [1,2]. Other risk factors include obesity, hyperlipidemia, and hypertension. Atherosclerosis can be considered to be a form of chronic inflammation involving responses of macrophages and lymphocytes to elevated levels of cholesterol [3]. Atherosclerosis is believed to be initiated by the oxidative modification of low density lipoprotein (LDL), which exerts numerous atherogenic effects on the artery wall [4]. Oxidized LDL (oxLDL) acts on endothelial cells to induce secretion of various chemokines, including MCP-1 and to up-regulate cell adhesion molecules, such as VCAM-1. Monocytes enter the vessel wall at these sites and migrate into the intima. While in the intima, the monocytes differentiate into macrophages and begin to take up oxLDL via scavenger receptors such as scavenger receptor A (SRA) and CD36 [5,6]. Unable to transport the oxLDL cholesterol out as rapidly as it is engulfed, these macrophages are transformed into “foam cells,” the hallmark of early atherosclerotic lesions. With progressive monocyte recruitment and uptake of oxLDL, foam cells become more numerous, resulting in the formation of fatty streaks. Smooth muscle cells can then begin to migrate into the intima and proliferate. These cells also take up modified LDL particles and synthesize extracellular matrix proteins, leading to the development of a fibrous cap. Necrosis and apoptosis of cells within the lesion result in the development of a necrotic core.