Role of NADPH Oxidase in Cytomegalovirus-Induced Proliferation of Human Coronary Artery Smooth Muscle Cells

Abstract

A number of infectious agents have been implicated in the development of vascular diseases such as atherosclerosis and posttransplantation arterial restenosis. Cytomegalovirus (CMV) has been reported to cause obliteration of coronary arteries by a progressive vasculopathy that involves proliferation of medial smooth muscle cells (SMC). In this study, we report that CMV enhances the serum-induced proliferation of human coronary SMC through activation of a superoxide-generating NADPH oxidase. Exposure of SMC to CMV for 2 h was associated with an 80% increase in NADPH oxidase. This increase in oxidase activity was associated with a two-fold increase in serum-induced DNA synthesis (5-bromo-2′-deoxyuridine incorporation) and significant interleukin-8 (IL-8) production by SMC. Diphenylene iodonium, an inhibitor of NADPH oxidase, significantly inhibited CMV-induced IL-8 production and promotion of serum-induced DNA synthesis. Similar effects were seen following pretreatment of SMC with N-acetyl cysteine, a potent antioxidant, suggesting that oxidative stress following CMV exposure might be responsible for triggering the proliferation of SMC. From this study, we conclude that CMV-mediated promotion of SMC growth is redox sensitive and may be mediated by NADPH oxidase.