From Inserm UMR 1087, CNRS UMR 6291 and University of Nantes, Nantes, France (M.L.C., J.B., G.C., P.P., G.L.); CHU Nantes, l'Institut du Thorax, Nantes, France (P.P., G.L.); Inserm, UMR 970, Paris Cardiovascular Research Center, Paris, France (N.D, X.J.); Université Paris Descartes, Sorbonne Paris Cité, Paris, France (A.B., M.A., X.J.); Assistance Publique, Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France (A.B., M.A., X.J.); Inserm CIC 1418, Paris, France (A.B., M.A.); and Laboratorio di Genomica e Proteomica funzionale, Universta di Bari, Bari, Italy (M.L.C.).
Hypertension. 2015 Jun;65(6):1273-8. doi: 10.1161/HYPERTENSIONAHA.114.05065. Epub 2015 Apr 13.
Although a causative role for RhoA-Rho kinase has been recognized in the development of human hypertension, the molecular mechanism(s) and the RhoA guanine exchange factor(s) responsible for the overactivation of RhoA remain unknown. Arhgef1 was identified as a RhoA guanine exchange factor involved in angiotensin II (Ang II)-mediated regulation of vascular tone and hypertension in mice. The aim of this study was to determine whether Arhgef1 is activated and involved in the activation of RhoA-Rho kinase signaling by Ang II in humans. In vitro stimulation of human coronary artery smooth muscle cells and human peripheral blood mononuclear cells by Ang II (0.1 μmol/L) induced activation of Arhgef1 attested by its increased tyrosine phosphorylation. Silencing of Arhgef1 expression by siRNA inhibited Ang II-induced activation of RhoA-Rho kinase signaling. In normotensive subjects, activation of the renin-angiotensin system by a low-salt diet for 7 days increased RhoA-Rho kinase signaling and stimulated Arhgef1 activity in peripheral blood mononuclear cells. In conclusion, our results strongly suggest that Arhgef1 mediates Ang II-induced RhoA activation in humans. Moreover, they show that measurement of RhoA guanine exchange factor activity in peripheral blood mononuclear cells might be a useful method to evaluate RhoA guanine exchange factor activity in humans.
虽然 RhoA- Rho 激酶在人类高血压的发展中起因果作用，但导致 RhoA 过度激活的分子机制和 RhoA 鸟嘌呤核苷酸交换因子仍然未知。Arhgef1 被鉴定为一种 RhoA 鸟嘌呤核苷酸交换因子，参与血管紧张素 II (Ang II) 介导的血管张力和高血压的调节。本研究旨在确定 Arhgef1 是否在人类中被激活，并参与 Ang II 对 RhoA-Rho 激酶信号的激活。Ang II (0.1 μmol/L) 在体外刺激人冠状动脉平滑肌细胞和人外周血单核细胞，通过其酪氨酸磷酸化增加证明 Arhgef1 被激活。用 siRNA 沉默 Arhgef1 的表达抑制 Ang II 诱导的 RhoA-Rho 激酶信号的激活。在正常血压受试者中，低盐饮食 7 天激活肾素-血管紧张素系统，增加 RhoA-Rho 激酶信号，并刺激外周血单核细胞中 Arhgef1 的活性。总之，我们的结果强烈表明，Arhgef1 在人类中介导 Ang II 诱导的 RhoA 激活。此外，它们表明测量外周血单核细胞中的 RhoA 鸟嘌呤核苷酸交换因子活性可能是评估人类 RhoA 鸟嘌呤核苷酸交换因子活性的有用方法。
