Published online before print November 5, 2007, doi: 10.1161/HYPERTENSIONAHA.106.084848
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(Hypertension. 2007;50:1093.)
© 2007 American Heart Association, Inc.
Original Articles |
Angiotensin-(1-7) Counterregulates Angiotensin II Signaling in Human Endothelial Cells
From the Department of Physiology (W.O.S., C.H.d.C., R.A.S.S.), Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Kidney Research Centre (C.H.d.C., R.M.T.), Ottawa Health Research Institute, University of Ottawa, Ontario, Canada; and Sir Mortimer B. Davis Research Institute-Jewish General Hospital (E.L.S.), McGill University, Quebec, Canada.
Correspondence to Rhian M. Touyz, Kidney Research Centre, University of Ottawa/Ottawa Health Research Institute, 451 Smyth Rd, Ottawa, Ontario, KIH 8M5 Canada. E-mail rtouyz{at}uottawa.ca
Angiotensin (Ang)-(1-7), acting through the Mas receptor, opposes the actions of Ang II. Molecular mechanisms for this are unclear. Here we sought to determine whether Ang-(1-7) influences Ang II signaling in human endothelial cells, focusing specifically on Src homology 2-containing inositol phosphatase 2 (SHP-2) and its interaction with c-Src. Ang II–induced phosphorylation of c-Src, extracellular signal regulated kinase (ERK)1/2, and SHP-2 and activation of NAD(P)H oxidase were assessed in the absence and presence of Ang-(1-7) (10–6 mol/L, 15 minutes) by immunoblotting and lucigenin-enhanced chemiluminescence, respectively. (D-Ala7)-Ang I/II (1-7) (Ang fragment 1-7 receptor antagonist) was used to block Ang-(1-7) effects. Association between SHP-2 and c-Src was assessed by immunoprecipitation/immunoblotting studies. Ang II significantly increased activation of c-Src, ERK1/2, and NAD(P)H oxidase and reduced phosphorylation of SHP-2 (P<0.05) in human endothelial cells. These effects were abrogated in cells pre-exposed to Ang-(1-7). Ang fragment 1-7 receptor antagonist pretreatment blocked the negative modulatory actions of Ang-(1-7) on Ang II–induced signaling. Ang-(1-7) alone did not significantly alter phosphorylation of c-Src, ERK1/2, and SHP-2 and had no effect on basal activity of NAD(P)H oxidase. SHP-2 and c-Src were physically associated in the basal state. This association was increased by Ang-(1-7) and blocked by Ang fragment 1-7 receptor antagonist. Our findings demonstrate that, in human endothelial cells, Ang-(1-7) negatively modulates Ang II/Ang II type 1 receptor–activated c-Src and its downstream targets ERK1/2 and NAD(P)H oxidase. We also show that SHP-2-c-Src interaction is enhanced by Ang-(1-7). These phenomena may represent a protective mechanism in the endothelium whereby potentially deleterious effects of Ang II are counterregulated by Ang-(1-7).
Key Words: Ang-(1-7) • Ang II signaling • Src • ERK1/2 • human endothelial cells • NO
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