4.7 Article

AMPK Alpha 1-Induced RhoA Phosphorylation Mediates Vasoprotective Effect of Estradiol

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LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.111.228304

关键词

cell physiology; g proteins; signal transduction; vasoconstriction; estrogen

资金

  1. Centre National de la Recherche Scientifique (CNRS)
  2. Institut National de la Sante et de la Recherche Medicale (INSERM)

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Objective-Estradiol (E2) mediates numerous beneficial effects assigned to estrogens, but whereas mechanisms have been described at the endothelial level, direct effects on vascular smooth muscle cells (VSMC) are poorly documented. As evidence accumulates regarding the role of RhoA in vascular pathophysiology and the benefit of RhoA-Rho associated protein kinase (Rock) pathway inhibition, we analyzed if E2 could inhibit it in VSMC. Methods and Results-We show that in VSMC, E2 inhibits the RhoA-Rock pathway in a time- and concentration-dependent manner. The inhibition of RhoA-Rock pathway results from E2-induced phosphorylation of the Ser188 of RhoA. Using pharmacological, transfection, and in vitro phosphorylation experiments, we demonstrate that AMP-activated protein kinase subunit alpha 1 (AMPK alpha 1) is activated by estrogen receptor stimulation and catalyzes RhoA phosphorylation induced by E2. Ex vivo, ovariectomy leads to an increase in the amplitude of phenylephrine-or serotonine-induced contractions of aortic rings in wild-type mice but not in AMPK alpha 1-knock-out mice or E2-supplemented animals. These functional effects were correlated with a reduced level of RhoA phosphorylation in the aorta of ovariectomized female, male, and AMPK alpha 1 knock-out mice. Conclusion-Our work thus defines AMPK alpha 1 as (1) a new kinase for RhoA and (2) a new mediator of the vasoprotective effects of estrogen. (Arterioscler Thromb Vasc Biol. 2011;31:2634-2642.)

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