期刊
NATURE MEDICINE
卷 16, 期 2, 页码 183-U89出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2079
关键词
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资金
- Institut National de la Sante et de la Recherche Medicale
- Agence Nationale de la Recherche [ANR-05-PCOD-015-01, ANR-08-GEN-O040-01]
- Fondation pour la Recherche Medicale [20051205767]
- Programme National de Recherche Maladies Cardiovasculaires
- Societe Francaise d'hypertension arterielle
- Centre National de la Recherche Scientifique
- Institut de Recherches Servier
Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, how RhoA is activated and whether it has a causative role in hypertension remains unclear. Here we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for angiotensin II-induced activation of RhoA signaling in arterial smooth muscle cells. We found that angiotensin II activates Arhgef1 through a previously undescribed mechanism in which Jak2 phosphorylates Tyr738 of Arhgef1. Arhgef1 inactivation in smooth muscle induced resistance to angiotensin II-dependent hypertension in mice, but did not affect normal blood pressure regulation. Our results show that control of RhoA signaling through Arhgef1 is central to the development of angiotensin II-dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension.
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