Macrophage apoptosis in atherosclerosis: consequences on plaque progression and the role of endoplasmic reticulum stress.

Atherothrombotic vascular diseases, such as myocardial infarction and stroke, are the leading causes of death in the industrialized world. The immediate cause of these diseases is acute occlusive thrombosis in medium-sized arteries feeding critical organs. Thrombosis is triggered by the rupture or erosion of a minority of atherosclerotic plaques that have advanced to a particular stage of "vulnerability." Vulnerable plaques are characterized by certain key features, such as inflammation, thinning of a protective collagenous cap, and a lipid-rich necrotic core consisting of macrophage debris. A number of cellular events contribute to vulnerable plaque formation, including secretion of pro-inflammatory, procoagulant, and proteolytic molecules by macrophages as well as the death of macrophages, intimal smooth muscles cells, and possibly endothelial cells. The necrotic core in particular is a key factor in plaque vulnerability, because macrophage debris promotes inflammation, plaque instability, and thrombosis. Plaque necrosis arises from a combination of lesional macrophage apoptosis and defective clearance of these dead cells, a process called efferocytosis. This review focuses on how macrophage apoptosis, in the setting of defective efferocytosis, contributes to necrotic core formation and how a process known to be prominent in advanced lesions--activation of ER stress signal-transduction pathways--contributes to macrophage apoptosis in these plaques.