Published online before print November 20, 2006, doi: 10.1161/01.HYP.0000251865.35728.2f
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(Hypertension. 2007;49:185.)
© 2007 American Heart Association, Inc.
Original Articles |
Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways
From the Department of Physiology (W.O.S., R.A.S.d.S., R.F.-S., L.T.d.M.M.), Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Sir Mortimer B. Davis-Jewish General Hospital (E.L.S.), McGill University, Quebec, Montreal, Canada; and the Kidney Research Centre (R.M.T.), Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, 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-(1-7) [Ang-(1-7)] causes endothelial-dependent vasodilation mediated, in part, by NO release. However, the molecular mechanisms involved in endothelial NO synthase (eNOS) activation by Ang-(1-7) remain unknown. Using Chinese hamster ovary cells stably transfected with Mas cDNA (Chinese hamster ovary-Mas), we evaluated the underlying mechanisms related to receptor Mas–mediated posttranslational eNOS activation and NO release. We further examined the Ang-(1-7) profile of eNOS activation in human aortic endothelial cells, which constitutively express the Mas receptor. Chinese hamster ovary-Mas cells and human aortic endothelial cell were stimulated with Ang-(1-7; 10–7 mol/L; 1 to 30 minutes) in the absence or presence of A-779 (10–6 mol/L). Additional experiments were performed in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin (10–6 mol/L). Changes in eNOS (at Ser1177/Thr495 residues) and Akt phosphorylation were evaluated by Western blotting. NO release was measured using both the fluorochrome 2,3-diaminonaphthalene and an NO analyzer. Ang-(1-7) significantly stimulated eNOS activation (reciprocal phosphorylation/dephosphorylation at Ser1177/Thr495) and induced a sustained Akt phosphorylation (P<0.05). Concomitantly, a significant increase in NO release was observed (2-fold increase in relation to control). These effects were blocked by A-779. Wortmannin suppressed eNOS activation in both Chinese hamster ovary-Mas and human aortic endothelial cells. Our findings demonstrate that Ang-(1-7), through Mas, stimulates eNOS activation and NO production via Akt-dependent pathways. These novel data highlight the importance of the Ang-(1-7)/Mas axis as a putative regulator of endothelial function.
Key Words: nitric oxide • human endothelial cells • NOS • Ang-(1-7) • angiotensin II
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