POSSIBLE PARTICIPATION OF FAS-MEDIATED APOPTOSIS IN THE MECHANISM OF ATHEROSCLEROSIS

Apoptosis is a programmed cell death that plays a major role during de velopment, homeostasis, and in many diseases. Recent evidence has demo nstrated the death of vascular smooth muscle cells (VSMCs) within adva nced human atheroma. In the rat balloon-injury model, apoptotic cells were specifically identified in the neointima. The presence of apoptot ic cells was demonstrated by in situ terminal deoxynucleotidyl transfe rase-mediated dUTP nick end labeling (TUNEL). To clarify the mechanism s that trigger apoptosis in atherosclerotic lesions, we examined wheth er cytokines released from macrophages can modulate Fas, a death signa l, in cultured human VSMCs. Simultaneous treatment with interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) but not with each c ytokine alone induced upregulation of Fas in VSMCs. However, coincubat ion with N-G-monomethyl-L-arginine, an inhibitor of nitric oxide (NO) synthesis, inhibited the upregulation of Fas induced by IL-1 and TNF-a lpha. Incubation with sodium nitroprusside, a NO donor, also induced u pregulation of Fas in VSMCs. Furthermore, fluorescent nuclear staining with Hoechst 33258 revealed that monoclonal antibody to human Fas sig nificantly enhanced NO-induced apoptotis in VSMCs. These findings sugg est that macrophage-derived cytokines can induce upregulation of Fas t hrough a NO-dependent mechanism in VSMCs. Thus, Fas-mediated apoptosis may regulate apoptotic death of VSMCs during atherogenesis.