Tumor Necrosis Factor-α Promotes Macrophage-Induced Vascular Smooth Muscle Cell Apoptosis by Direct and Autocrine Mechanisms

Abstract

Objective— We have previously shown that human macrophages induce human plaque vascular smooth muscle cell (VSMC) apoptosis by cell-cell proximity, Fas-L, and nitric oxide (NO), thereby predisposing to plaque rupture. This study sought to analyze whether tumor necrosis factor-α (TNF-α) contributes additionally to macrophage-induced VSMC apoptosis. Methods and Results— Macrophage-induced VSMC apoptosis was examined in direct coculture. Antagonistic antibodies to TNF-receptor (R1) inhibited VSMC apoptosis, and preincubation of monocytes and VSMCs indicated that TNF-R1 on both cell types contributed to macrophage-induced VSMC apoptosis. Correspondingly, both monocytes and VSMCs expressed TNF-R1, and macrophages expressed cell surface TNF-α. Two NO donors upregulated VSMC surface TNF-R1, and exogenous TNF-α induced VSMC apoptosis synergistically with the NO donor diethylenetriamine/NO, indicating that NO sensitizes VSMCs to TNF-α. Neutralizing anti–TNF-R1 antibodies inhibited macrophage activation assessed by Fas-L expression and NO secretion. Conclusions— TNF-α promotes macrophage-induced VSMC apoptosis by autocrine and direct pathways.