S-glutathiolation of Ras mediates redox-sensitive signaling by angiotensin II in vascular smooth muscle cells

被引:239
作者
Adachi, T
Pimentel, DR
Heibeck, T
Hou, XY
Lee, YJ
Jiang, BB
Ido, Y
Cohen, RA
机构
[1] Boston Univ, Med Ctr X707, Whitaker Cardiovasc Inst, Vasc Biol Unit, Boston, MA 02118 USA
[2] Boston Univ, Med Ctr, Whitaker Cardiovasc Inst, Myocardial Biol Unit, Boston, MA 02118 USA
[3] Boston Univ, Med Ctr, Whitaker Cardiovasc Inst, Diabet & Metab Unit, Boston, MA 02118 USA
[4] Univ Pittsburgh, Hillman Canc Ctr, Dept Surg, Pittsburgh, PA 15260 USA
[5] Univ Pittsburgh, Hillman Canc Ctr, Inst Canc, Pittsburgh, PA 15260 USA
关键词
D O I
10.1074/jbc.M313320200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Angiotensin II (AII) increases production of reactive oxygen species from NAD(P) H oxidase, a response that contributes to vascular hypertrophy. Here we show in cultured vascular smooth muscle cells that S-glutathiolation of the redox-sensitive Cys(118) on the small GTPase, Ras, plays a critical role in AII-induced hypertrophic signaling. AII simultaneously increased the Ras activity and the S-glutathiolation of Ras (GSS-Ras) detected by biotin-labeled GSH or mass spectrometry. Both the increase in activity and GSS-Ras was labile under reducing conditions, suggesting the essential nature of this thiol modification to Ras activation. Overexpression of catalase, a dominant-negative p47(phox), or glutaredoxin-1 decreased GSS-Ras, Ras activation, p38, and Akt phosphorylation and the induction of protein synthesis by AII. Furthermore, expression of a Cys(118) mutant Ras decreased AII-mediated p38 and Akt phosphorylation as well as protein synthesis. These results show that H2O2 from NAD( P) H oxidase forms GSS-Ras on Cys(118) and increases its activity leading to p38 and Akt phosphorylation, which contributes to the induction of protein synthesis. This study suggests that GSS-Ras is a redox-sensitive signaling switch that participates in the cellular response to AII.
引用
收藏
页码:29857 / 29862
页数:6
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