An Oxidized Extracellular Redox State Increases Nox1 Expression and Proliferation in Vascular Smooth Muscle Cells via EGFR Activation

Objective—Generation of reactive oxygen species (ROS) by Nox-based NADPH oxidases activate redox-dependent signaling pathways and contribute to development of “oxidative stress ” in vascular disease. An oxidized plasma redox state is associated with cardiovascular disease in humans, however; cellular mechanisms by which extracellular redox state may cause disease are not known. In this study, we examined the effect of an oxidized extracellular redox state (Eh) on expression of NADPH oxidases in vascular cells. Methods and Results—Aortic segments and cultured aortic smooth muscle cells (SMCs) 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 expression of Nox1 and resulted in Nox1-dependent proliferation of SMCs. Oxidized Eh rapidly induced epidermal growth factor receptor (EGFR) phosphorylation via shedding of EGF-like ligands from the plasma membrane and caused extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent phosphorylation of the transcription factors activating transcription factor-1 (ATF-1) and cAMP-response-element-binding protein (CREB). Inhibition of EGFR or ERK1/2 activation, o