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Angiotensin II type 2 receptor activation induces RhoA inhibition through Phosphorylation of its Serine 188 in Vascular Smooth Muscle Cells
Author(s) -
RolliDerkinderen Malvyne,
Guilluy Christophe,
Loufrani Laurent,
Henrion Daniel,
Loirand Gervaise,
Pacaud Pierre
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a105
Subject(s) - rhoa , phosphorylation , angiotensin ii , vascular smooth muscle , chemistry , agonist , receptor , microbiology and biotechnology , serine , signal transduction , endocrinology , medicine , biology , biochemistry , smooth muscle
Angiotensin II (Ang II) plays important roles in the control of blood pressure. Evidences indicate that Ang II type 2 receptor (AT2R) antagonizes the effects of type 1 receptor (AT1R) and inactivation of RhoA signaling has been suggested to be involve in this action. As serine 188 phosphorylation of RhoA inhibits its activity, we analyzed the effect of Ang II on RhoA phosphorylation both in vitro and in vivo. In rat aortic smooth muscle cells (VSMC), Ang II (0.1 μM) induces serine‐phosphorylation of RhoA. This effect is abolished by the AT2R antagonist PD 123319, mimicked by the AT2R agonist CGP42112A and does not involved NOS, PKA or PKG. S188A‐ or S188E‐RhoA mutants expressed in VSMC are not phosphorylated by AT2R stimulation indicating that AT2R activation promotes phosphorylation of RhoA on Ser 188. AT2R‐induced phosphorylation of RhoA is associated to an increased binding to the guanidine dissociation inhibitor GDI, leading to inactivation of RhoA/Rho kinase signaling. In vivo, inhibition of AT1R has been shown to up‐regulate AT2R expression. We shown that in aorta and pulmonary artery of WKY and SHR, Ser 188 phosphorylation of RhoA is strongly increased in animals treated with the AT1R inhibitor candesartan (2wks, 2 mg/kg/d). Our results thus indicate that AT2R stimulation induces phosphorylation of RhoA on Ser 188, leading to RhoA inactivation through increased association to cytosolic GDI. In vivo experiments suggest that AT2R‐mediated inhibition of RhoA by Ser 188 phosphorylation may contribute to the antihypertensive effect of AT1R inhibitors. American Physiological Society