H2O2 Regulation of Vascular Function Through sGC mRNA Stabilization by HuR

Objective-Hydrogen peroxide (H2O2) is an important mediator in the vasculature, but its role in the regulation of soluble guanylate cyclase (sGC) activity and expression is not completely understood. The aim of this study was to test the effect of H2O2 on sGC expression and function and to explore the molecular mechanism involved. Methods and Results-H2O2 increased sGC beta 1 protein steady-state levels in rat aorta and aortic smooth muscle cells (RASMCs) in a time-and dose-dependent manner, and this effect was blocked by catalase. sGC alpha 2 expression increased along with beta 1 subunit, whereas alpha 1 subunit remained unchanged. Vascular relaxation to an NO donor (sodium nitroprusside) was enhanced by H2O2, and it was prevented by ODQ (sGC inhibitor). cGMP production in both freshly isolated vessels and RASMCs exposed to H2O2 was greatly increased after sodium nitroprusside treatment. The H2O2-dependent sGC beta 1 upregulation was attributable to sGC beta 1 mRNA stabilization, conditioned by the translocation of the mRNA-binding protein HuR from the nucleus to the cytosol, and the increased mRNA binding of HuR to the sGC beta 1 3' untranslated region. HuR silencing reversed the effects of H2O2 on sGC beta 1 levels and cGMP synthesis. Conclusion-Our results identify H2O2 as an endogenous mediator contributing to the regulation of vascular tone and point to a key role of HuR in sGC beta 1 mRNA stabilization. (Arterioscler Thromb Vasc Biol. 2011;31:567-573.)