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

作者：Stanic Bojana; Katsuyama Masato; Miller Francis J Jr^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2010, 30(11): 2234-U486.

DOI：10.1161/ATVBAHA.110.207639

• oxidative stress
• atherosclerosis
• NADPH oxidase
• epidermal growth factor receptor

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 epidermal growth factor-like ligands from the plasma membrane and caused extracellular signal-regulated kinase 1/2-dependent phosphorylation of the transcription factors activating transcription factor-1 and cAMP-response element-binding protein. Inhibition of epidermal growth factor receptor or extracellular signal-regulated kinase 1/2 activation, or addition of small interference RNA to activating transcription factor-1, prevented the increase in Nox1 expression.
Conclusion-Our results identify a novel mechanism by which extracellular oxidative stress increases expression and activity of Nox1 NADPH oxidase and contributes to vascular disease. (Arterioscler Thromb Vasc Biol. 2010; 30: 2234-2241.)

• 出版日期2010-11