Apoptosis and plaque destabilization in atherosclerosis: the role of macrophage apoptosis induced by cholesterol

Macrophages are the most prominent cell type in atherosclerotic lesions, and a portion of these cells become apoptotic, particularly in advanced lesions. One inducer of apoptosis in atherosclerosis is the accumulation of large amounts of intracellular unesterified or ‘free’ cholesterol (FC). A portion of the FC accumulates in the endoplasmic reticulum (ER) membrane, which is normally cholesterol poor and highly fluid. This event, probably by altering the function of integral ER membrane proteins, induces the ER stress signal transduction pathway, known as the unfolded protein response (UPR). A branch of the UPR eventually leads to an apoptotic response in the macrophages, which is mediated by both Fas and mitochondrial pathways. In vivo evidence suggests that this chain of eventsmay promote plaque destabilization in advanced atherosclerotic lesions, which is ultimately responsible for acute atherothrombotic vascular occlusion and tissue infarction. © 2004, Nature Publishing Group. All rights reserved.