title: Resveratrol prevents AngII-induced hypertension via AMPK activation and RhoA/ROCK suppression in mice.
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.
authors: Department of Obstetrics and Gynecology, the Fourth Hospital of Chinese Medical University, Shenyang, China.
authors: Xia
authors: X
authors: Cao
authors: Department of Obstetrics and Gynecology, the Fourth Hospital of Chinese Medical University, Shenyang, China.
authors: Tao
authors: T
authors: Luo
authors: Department of Obstetrics and Gynecology, the Fourth Hospital of Chinese Medical University, Shenyang, China.
authors: Xi
authors: X
authors: Luo
authors: Department of Obstetrics and Gynecology, the Fourth Hospital of Chinese Medical University, Shenyang, China.
authors: Zhiyi
authors: Z
authors: Tang
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D013267:Stilbenes; D000804:Angiotensin II; D054460:rho-Associated Kinases; D000263:Adenylate Kinase; D020742:rhoA GTP-Binding Protein; D000077185:Resveratrol