Resveratrol via activation of AMPK lowers blood pressure in DOCA-salt hypertensive mice

摘要

Objective: Resveratrol, a phytoalexin, is reported to activate AMP-activated protein kinase (AMPK) in vascular cells. Activation of AMPK induces vasorelaxation to lower blood pressure (BP). Whether resveratrol via activation of AMPK decreases, BP remains unknown. Methods: Male wild-type (WT) mice and mice deficient in AMPK2 (AMPK2(-/-)) were fed with resveratrol (400mg/kg). After 7d, mice were implanted with deoxycorticosterone acetate (DOCA)-salt (150mg/kg) for 35d. BP was detected by the radiotelemetry method. Vessel contraction was determined by organ chamber. Active RhoA, Rho-associated kinase (ROCK) activity, phosphorylations of myosin light chain (MLC), and myosin phosphatase targeting subunit 1 (MYPT1) were assayed by western blot. Results: Implantation of DOCA-salt dramatically increased systemic BPs (systolic BP and diastolic BP) in WT and AMPK2(-/-) mice. However, treatment of resveratrol significantly decreased systemic BP in WT mice but not in AMPK2(-/-) mice. In the organ chamber study, resveratrol inhibited agonist-induced vessel relaxation in WT mice aortas. Loss of AMPK2 or AMPK inhibition by compound C reversed resveratrol-suppressed vasoconstriction in isolated mice aortas. In cultured vascular smooth muscle cells (VSMCs), activation of AMPK by resveratrol inhibited phenylephrine-enhanced MLC phosphorylation in a dose-dependent manner. Conclusions: Resveratrol via activation of AMPK lowers BP in DOCA-hypertensive mice through an AMPK/RhoA/ROCK2/MLCMLC pathway.