NADPH oxidase 4 mediates TGF-β-induced smooth muscle α-actin via p38MAPK and serum response factor

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• 作者：Abel Martin-Garrido^a ; David I. Brown^a ; Alicia N. Lyle^a ; Anna Dikalova^a ; Bonnie Seidel-Rogol^a ; Bernard Lass&#xe8 ; gue^a ; Alejandra San Martí ; n^a ; Kathy K. Griendling ; ^a ; ^{kgriend@emory.edu}
• 关键词：Vascular smooth muscle ; Smooth muscle α ; -actin ; Transforming growth factor-β ; NADPH oxidase 4 ; Serum response factor ; Reactive oxygen species ; p38 mitogen-activated protein kinase ; Free radicals
• 刊名：Free Radical Biology and Medicine
• 出版年：2011
• 出版时间：15 January 2011
• 年：2011
• 卷：50
• 期：2
• 页码：354-362
• 全文大小：1215 K

文摘

In contrast to other cell types, vascular smooth muscle cells modify their phenotype in response to external signals. NADPH oxidase 4 (Nox4) is critical for maintenance of smooth muscle gene expression; however, the underlying mechanisms are incompletely characterized. Using smooth muscle α-actin (SMA) as a prototypical smooth muscle gene and transforming growth factor-β (TGF-β) as a differentiating agent, we examined Nox4-dependent signaling. TGF-β increases Nox4 expression and activity in human aortic smooth muscle cells (HASMC). Transfection of HASMC with siRNA against Nox4 (siNox4) abolishes TGF-β-induced SMA expression and stress fiber formation. siNox4 also significantly inhibits TGF-β-stimulated p38MAPK phosphorylation, as well as that of its substrate, mitogen-activated protein kinase-activated protein kinase-2. Moreover, the p38MAPK inhibitor SB-203580 nearly completely blocks the SMA increase induced by TGF-β. Inhibition of either p38MAPK or NADPH oxidase-derived reactive oxygen species impairs the TGF-β-induced phosphorylation of Ser103 on serum response factor (SRF) and reduces its transcriptional activity. Binding of SRF to myocardin-related transcription factor (MRTF) is also necessary, because downregulation of MRTF by siRNA abolishes TGF-β-induced SMA expression. Taken together, these data suggest that Nox4 regulates SMA expression via activation of a p38MAPK/SRF/MRTF pathway in response to TGF-β.