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  • Title: Resveratrol prevents AngII-induced hypertension via AMPK activation and RhoA/ROCK suppression in mice.
    Author: Cao X, Luo T, Luo X, Tang Z.
    Journal: Hypertens Res; 2014 Sep; 37(9):803-10. PubMed ID: 24965170.
    Abstract:
    The purpose of this study was to determine the effects of resveratrol (RSV) and the molecular mechanisms by which it regulates vascular smooth muscle contraction and blood pressure in mice. In cultured human vascular smooth muscle cells (VSMCs), we found that the activation of AMP-activated protein kinase (AMPK) by RSV inhibited angiotensin II (AngII)-induced phosphorylation of myosin phosphatase-targeting subunit 1 (MYPT1) and myosin light chain (MLC). Inversely, AMPK inhibition with RNA interference and compound C, an AMPK inhibitor, abolished the inhibitory effect of RSV on AngII-induced MYPT1 and MLC phosphorylation. Thiazovivin, a Rho-associated kinase (ROCK) inhibitor, reversed AngII-induced MYPT1 and MLC phosphorylation, suggesting that ROCK functions as an upstream kinase for MYPT1/MLC. RSV reversed AngII-induced Ras homolog gene family member A (RhoA) and ROCK activity, whereas AMPK inhibition via pharmacological or genetic means abolished this effect. In addition, gene silencing of p190-guanosine triphosphatase-activating protein blocked the effects of RSV-induced AMPK activation on MLC, MYPT1 and RhoA in VSMCs. Ex vivo analyses demonstrated that AngII-induced aorta contractions were dramatically inhibited by RSV, and this effect was abolished by AMPK inhibition. Finally, daily chronic administration of RSVl alleviated hypertension in the experimental model of AngII-induced hypertensive mice, and these effects were accompanied by the activation of AMPK, significantly decreased RhoA activity and phosphorylation levels of MYPT1 and MLC in AngII-treated murine aortic VSMCs. More importantly, administration of compound C significantly abolished the effects of RSV. In conclusion, AMPK suppression of the p190-GAP-dependent RhoA/ROCK/MYPT1/MLC pathway contributes to the hypotensive effect of RSV in AngII-treated mice.
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