Published online before print May 4, 2009
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Departments of Medicine, Pathology and Cell Biology and Physiology and Cellular Biophysics, Columbia University, New York, New York, USA
1. Correspondence: Department of Medicine, 630 West 168th St., Columbia University, New York, NY 10032, USA. E-mail: iat1{at}columbia.edu
ABSTRACT
Throughout atherosclerotic lesion development, intimal macrophages undergo apoptosis, a form of death that usually prevents cellular necrosis. In advanced atherosclerotic lesions, however, these apoptotic macrophages become secondarily necrotic and coalesce over time into a key feature of vulnerable plaques, the necrotic core. This event is critically important, as necrotic core formation in these advanced atheromata is thought to promote plaque disruption and ultimately, acute atherothrombotic vascular disease. Increasing evidence suggests that the mechanism behind postapoptotic macrophage necrosis in advanced atherosclerosis is defective phagocytic clearance or "efferocytosis" of the apoptotic cells. Thus, understanding the cellular and molecular mechanisms of efferocytosis in atherosclerosis and why efferocytosis becomes defective in advanced lesions is an important goal. Molecular–genetic causation studies in mouse models of advanced atherosclerosis have provided evidence that several molecules known to be involved in efferocytosis, including TG2, MFG-E8, complement C1q, Mertk, lysoPC, and Fas, play important roles in the clearance of apoptotic cells in advanced plaques. These and future insights into the molecular mechanisms of defective efferocytosis in advanced atheromata may open the way for novel therapeutic strategies for atherothrombotic vascular disease, the leading cause of death in the industrialized world.
Key Words: apoptosis • phagocytosis • macrophage • necrosis • Mertk • milk fat globule-epidermal growth factor 8 (MFG-E8 • lactadherin) • transglutaminase 2 • complement C1q • Fas • lysophosphatidylcholine
