Tumor necrosis factor-α promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms

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-alpha (TNF-alpha) 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-alpha. Two NO donors upregulated VSMC surface TNF-R1, and exogenous TNF-alpha induced VSMC apoptosis synergistically with the NO donor diethylenetriamine/NO, indicating that NO sensitizes VSMCs to TNF-alpha. Neutralizing anti-TNF-R1 antibodies inhibited macrophage activation assessed by Fas-L expression and NO secretion. Conclusions - TNF-alpha promotes macrophage-induced VSMC apoptosis by autocrine and direct pathways.