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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1624.)
© 2002 American Heart Association, Inc.

Vascular Biology

Human Macrophage-Induced Vascular Smooth Muscle Cell Apoptosis Requires NO Enhancement of Fas/Fas-L Interactions

Joseph J. Boyle; Peter L. Weissberg; Martin R. Bennett

From the Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, UK.

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

Objective— We have previously shown that macrophages induce vascular smooth muscle cell (VSMC) apoptosis in vitro by cell-cell proximity and Fas-L/Fas interactions. Because NO is a short-range mediator, we tested whether NO mediates macrophage-induced VSMC apoptosis.

Methods and Results— NO synthase (NOS) inhibitors markedly inhibited macrophage-induced apoptosis of carotid plaque VSMCs (apoptotic indices, 81±2.9% for control and 28.2±3.9% for N^G-nitro-L-arginine methyl ester [L-NAME] treatment) and coronary medial VSMCs (apoptotic indices, 76±5.5% for control and 3.5±0.8% for L-NAME treatment). Inactive enantiomers were without effect (P>0.05). Cultured macrophages, but not VSMCs, expressed inducible NOS (but not neuronal NOS or endothelial NOS) concomitant with activation and secreted 1.51±0.3 fmol nitrite per cell, which was blocked by L-NAME (100 µmol/L). Diethylene triamine nitric oxide (DETA/NO) and sodium nitroprusside (NO donors) induced VSMC cell-surface Fas and enhanced plaque VSMC apoptosis induced by agonistic anti-Fas antibody (apoptotic indices, 6.6±1.8% for control, 6.3±1.5% for DETA/NO, 26±1.8% for Fas, and 44±6.9% for Fas+DETA/NO). In isolated macrophages, NOS inhibitors reduced and NO donors increased surface Fas-L, indicating an NO-dependent autocrine enhancement of macrophage surface Fas-L.

Conclusions— Together, these data indicate that macrophage-derived NO is required for macrophage-induced VSMC apoptosis and that it acts by enhancing Fas-L/Fas interactions.

Key Words: macrophages • plaque rupture • vascular smooth muscle cells • nitric oxide • Fas

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