title: Angiotensin II activates the RhoA exchange factor Arhgef1 in humans.
abstract: 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.
authors: 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.).
authors: Maria Luigia
authors: ML
authors: Carbone
authors: 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.).
authors: Jérémy
authors: J
authors: Brégeon
authors: 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.).
authors: Nabila
authors: N
authors: Devos
authors: 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.).
authors: Gilliane
authors: G
authors: Chadeuf
authors: 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.).
authors: Anne
authors: A
authors: Blanchard
authors: 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.).
authors: Michel
authors: M
authors: Azizi
authors: 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.).
authors: Pierre
authors: P
authors: Pacaud
authors: 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.).
authors: Xavier
authors: X
authors: Jeunemaître
authors: 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.). gervaise.loirand@univ-nantes.fr.
authors: Gervaise
authors: G
authors: Loirand
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D064067:Rho Guanine Nucleotide Exchange Factors; D000804:Angiotensin II; D020742:rhoA GTP-Binding Protein
keywords: Rho GTP-binding proteins; Rho guanine nucleotide exchange factors; angiotensins; arteries; hypertension; leukocytes; signal transduction