Peroxisome Proliferator–Activated Receptor-γ Ligands Inhibit Nitric Oxide Synthesis in Vascular Smooth Muscle Cells

—Peroxisome proliferator–activated receptor-γ (PPARγ) is a key player in glucose metabolism. If PPARγ ligands modulate nitric oxide (NO) synthesis in the vascular tissue, they may affect the process of plaque formation and postangioplasty restenosis. We investigated the effects of PPARγ ligands on NO synthesis in vascular smooth muscle cells. Incubation of cultures with interleukin-1β (10 ng/mL) for 24 hours caused a significant increase in the production of nitrite, a stable metabolite of NO, in cultured rat vascular smooth muscle cells. The PPARγ agonists troglitazone and 15-deoxy-▵12,14 -prostaglandin J2 (15d-PG J2 ) dose-dependently inhibited nitrite production by interleukin-1β–stimulated vascular smooth muscle cells. Decreased interleukin-1β–induced nitrite production by the PPARγ agonists was accompanied by decreased inducible NO synthase mRNA and protein accumulation. Interleukin-1β induced nuclear factor-κB activation in vascular smooth muscle cells, and both troglitazone and 15d-PG J2 markedly suppressed this nuclear factor-κB activation. PPARγ ligands inhibit NO synthesis in cytokine-stimulated vascular smooth muscle cells, suggesting that these agonists may act directly on the vascular smooth muscle and influence the process of atherosclerosis and restenosis.