Neopterin Induces Nitric Oxide-Dependent Apoptosis in Rat Vascular Smooth Muscle Cells

Abstract

Numerous studies indicate that proinflammatory substances like tumor necrosis factor a (TNF(x) and interferon y (IFN-y) as well as macrophage-derived neopterin are increased in atherosclerotic tissue and thus are potentially involved in the process of atherogenesis.Since apoptotic death of vascular smooth muscle cells (VSMC) is reported to occur in atherosclerotic lesions, we investigated the effects of neopterin, TNF-a, and IFN-y on apoptosis in cultured VSMC.Morphological changes characteristic of apoptosis as well as DNA fragmentation were detected in cells treated with neopterin, TNF-a/IFN-y, and neopterin + TNF-oc/IFN-'y.Simultaneously, neopterin, TNF-oc/IFN-y, and neopterin + TNF-a/IFN-y led to inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) synthesis.NO generation was significantly reduced when cells were cotreated with the competitive iNOS inhibitor aminoguanidine.This was accompanied by decreased percentual apoptosis as detected by FACS analysis using all kinds of stimuli.We conclude that neopterin as well as TNF-a/IFN-y are potent mediators of apoptotic death in VSMC which is at least in part triggered by NO synthesis induced by these proinflammatory mediators.