An oxidized extracellular oxidation-reduction state increases Nox1 expression and proliferation in vascular smooth muscle cells via epidermal growth factor receptor activation.

Journal Article (Journal Article)

OBJECTIVE: To examine the effect of an oxidized extracellular oxidation-reduction (redox) state (E(h)) 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 E(h) 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 E(h) increased the expression of Nox1 and resulted in Nox1-dependent proliferation of smooth muscle cells. Oxidized E(h) 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. CONCLUSIONS: Our results identify a novel mechanism by which extracellular oxidative stress increases expression and activity of Nox1 NADPH oxidase and contributes to vascular disease.

Full Text

Duke Authors

Cited Authors

  • Stanic, B; Katsuyama, M; Miller, FJ

Published Date

  • November 2010

Published In

Volume / Issue

  • 30 / 11

Start / End Page

  • 2234 - 2241

PubMed ID

  • 20814013

Pubmed Central ID

  • PMC2959123

Electronic International Standard Serial Number (EISSN)

  • 1524-4636

Digital Object Identifier (DOI)

  • 10.1161/ATVBAHA.110.207639


  • eng

Conference Location

  • United States