Macrophage Cholesterol Homeostasis and Atherogenesis: Critical Role of Intracellular Cholesteryl Ester Hydrolysis

Abstract

Coronary artery disease (CAD) is the leading cause of death in United States and contributes to significant mortality around the world. According to the Heart Disease and Stroke 2011 update, released by the American Heart Association, 82,600,000 American adults (>1 in 3) have 1 or more type of cardiovascular disease and >2200 Americans die of CAD every day which is an average of 1 in every 39 seconds. These are alarming statistics and underscore the importance of continued understanding of the processes involved in the development of CAD. Atherosclerosis, characterized by increased lipid accumulation in the artery wall, is the major underlying cause of CAD. Atherosclerosis is a chronic disease that often starts during early teens and progresses silently without any overt clinical symptoms till about age 40 when it manifests as heart attack or even stroke. While it is well established that accumulation of lipid-laden macrophage foam cells in the artery wall is the hall mark of atherosclerosis, two different theories are proposed to describe the events leading to infiltration of macrophages and subsequent development of foam cells within the artery wall. According to “response to injury” hypothesis, the initiating event is injury to the endothelial lining of the artery wall leading to the subsequent migration of monocytes and circulating lipoproteins mainly the low density lipoprotein (LDL) into the intimal space. This is followed by the unregulated uptake of modified LDL (mLDL) by monocyte derived macrophages leading to the formation of foam cells (Ross et al, 1977, Ross, 1993). “Response to retention” hypothesis, on the other hand, proposes that LDL migrates into the intimal space and is retained by association with the proteoglycans and is modified. Subsequent uptake by infiltrating macrophages results in development of foam cells (Williams and Tabas, 1995). Regardless of the sequence of events, the end result is accumulation of foam cells in the intimal space of the artery wall. This initiates the formation of fatty streaks which develops into an atherosclerotic plaque with continued accretion of foam cells. Figure 1 below summarizes these major events that lead to the formation of atherosclerotic plaque. Continuous accumulation of lipid laden foam cells in an atherosclerotic plaque not only contributes to its volume but also enhances plaque associated inflammation and thus determines its vulnerability to rupture (Davies and Thomas, 1985). Therefore, reduction in the lipid core of the plaque is an obvious strategy to target reduction in plaque volume as