Glutaredoxin mediates Akt and eNOS activation by flow in a glutathione reductase-dependent manner.

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Wang J, Pan S, Berk BC

Glutaredoxin mediates Akt and eNOS activation by flow in a glutathione reductase-dependent manner.

Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1283-8. Epub 2007 Apr 12.

PubMed ID

17431186 [ View in PubMed

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Abstract

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/cm2) 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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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Glutathione	Glutaredoxin-1	Protein	Humans	Unknown	Not Available	Details