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

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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.