The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure
The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure
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DOI：
10.1038/nm.2079
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发表时间：
2010-02-01
期刊：
影响因子：
82.9
通讯作者：
Loirand, Gervaise
中科院分区：
文献类型：
--
作者：
Guilluy, Christophe;Bregeon, Jeremy;Loirand, Gervaise
高血压是工业化国家最常见的疾病之一。虽然被认为是依赖于遗传和环境因素的组合，其分子基础仍然难以捉摸。动脉中单体G蛋白RhoA的活性增加是高血压的常见特征。然而，RhoA是如何被激活的，以及它是否在高血压中起致病作用仍不清楚。在这里，我们提供的证据表明，Arhgef1是RhoA鸟嘌呤交换因子，特别是负责血管紧张素II诱导的激活动脉平滑肌细胞中的RhoA信号。我们发现，血管紧张素II通过以前未描述的机制激活Arhgef1，其中Jak2磷酸化Arhgef1的Tyr738。平滑肌中的Arhgef1失活诱导小鼠对血管紧张素II依赖性高血压的抵抗，但不影响正常的血压调节。我们的研究结果表明，通过Arhgef1控制RhoA信号传导是血管紧张素II依赖性高血压的发展的核心，并确定Arhgef1作为治疗高血压的潜在靶点。
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.