期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 27, 期 6, 页码 1283-1288出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.144659
关键词
Grx; Akt; eNOS; GR; endothelial cells
资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL077789] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL 77789] Funding Source: Medline
Objective-The glutathione (GSH)/glutaredoxin (Grx) system regulates activities of many redox sensitive enzymes. This system has been shown to protect cells from hydrogen peroxide-induced apoptosis by regulating the redox state of Akt. Grx can be regulated by redox state; the oxidized Grx is selectively recycled to the reduced form by GSH. Flow can maintain endothelial cells in a reduced state by activating glutathione reductase (GR) and increasing the GSH/GSSG ratio. Because steady laminar flow exerts an antioxidant effect, we hypothesized that Grx mediates flow induced Akt and eNOS phosphorylation in a GR dependent manner. Methods and Results-Exposure of endothelial cells (ECs) to physiological steady laminar flow (shear stress = 12 dyn/cm(2)) for 5 minutes significantly increased Grx activity (1.9 +/- 0.2-fold), and also increased Akt and eNOS phosphorylation. Overexpression of GFP-GR in ECs significantly increased Grx activity by 1.6 +/- 0.1-fold. Pretreatment with the GR inhibitor 1,3-bis[2-chloroethyl]-1-nitrosourea (BCNU) for 30 minutes dramatically reduced Grx activity and inhibited the increase in Akt and eNOS phosphorylation induced by flow. Overexpression of wild-type Grx in ECs increased both Akt and eNOS phosphorylation. In contrast, a mutated Grx (C22S/C25S), which lacks thioltransferase activity, had no effect. Therefore, flow-induced Akt and eNOS phosphorylation depend on Grx thioltransferase activity. Downregulation of Grx by small interfering RNA decreased flow induced Akt and eNOS phosphorylation. Conclusions-These data suggest that Grx is an important mediator for flow-induced Akt and eNOS activation, and Grx activity depends on GR-mediated changes in EC redox state.
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