An Oxidized Extracellular Oxidation-Reduction State Increases Nox1 Expression and Proliferation in Vascular Smooth Muscle Cells Via Epidermal Growth Factor Receptor Activation

Abstract

Objective—To examine the effect of an oxidized extracellular oxidation-reduction (redox) state (Eh) on the expression of NADPH oxidases in vascular cells. Methods and Results—The generation of reactive oxygen species by NADPH oxidase (Nox)-based NADPH oxidases activates redox-dependent signaling pathways and contributes to the development of “oxidative stress” in vascular disease. An oxidized plasma redox state is associated with cardiovascular disease in humans; however, the cellular mechanisms by which the extracellular redox state may cause disease are not known. Aortic segments and cultured aortic smooth muscle cells were exposed to Eh between −150 mV (reduced) and 0 mV (oxidized) by altering the concentration of cysteine and its disulfide, cystine, the predominant redox couple in plasma. A more oxidized Eh increased the expression of Nox1 and resulted in Nox1-dependent proliferation of smooth muscle cells. Oxidized Eh rapidly induced epidermal growth factor receptor phosphorylation via shedding of ep...