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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1402.)
© 2001 American Heart Association, Inc.

Vascular Biology

Human Blood-Derived Macrophages Induce Apoptosis in Human Plaque-Derived Vascular Smooth Muscle Cells by Fas-Ligand/Fas Interactions

Joseph J. Boyle; David E. Bowyer; Peter L. Weissberg; Martin R. Bennett

From the Unit of Cardiovascular Medicine, Addenbrooke’s Hospital (J.J.B., P.L.W., M.R.B.), and the Department of Pathology, University of Cambridge (D.E.B.), Cambridge, UK.

Correspondence to Dr J.J. Boyle, Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK. E-mail joseph.boyle{at}ic.ac.uk

Abstract—— Human atherosclerotic plaques that rupture are characterized by relatively low vascular smooth muscle cell (VSMC) and high inflammatory cell contents. Ruptured plaques also contain higher numbers of apoptotic VSMCs than do stable lesions, suggesting that VSMC apoptosis may promote plaque rupture. We examined the ability of human monocytes/macrophages to induce apoptosis of VSMCs derived from human carotid plaque, aortic media, and coronary media. Macrophages, but not T lymphocytes, induced a dose-dependent apoptosis of VSMCs, which required monocyte maturation to macrophages and direct cell-cell contact/proximity. VSMC apoptosis was inhibited by neutralizing antibodies to Fas-ligand (Fas-L) or an Fas-Fc fusion protein, indicating the requirement for membrane-bound Fas and Fas-L. Monocyte maturation was associated with increased surface expression of Fas-L, coincident with the onset of cytotoxicity. VSMCs expressed surface Fas, which was increased in plaque VSMCs, and plaque VSMCs also underwent Fas-induced apoptosis. We conclude that human macrophages potently induce human VSMC apoptosis, which requires direct cell-cell interactions and is in part dependent on Fas/Fas-L interactions. Macrophage-induced VSMC apoptosis may therefore directly promote plaque rupture.

Key Words: macrophages • atherosclerosis • apoptosis • smooth muscle cells, vascular • Fas