Hypertension. 2005;45:773-779
Published online before print February 7, 2005,
doi: 10.1161/01.HYP.0000154365.30593.d3
(Hypertension. 2005;45:773.)
© 2005 American Heart Association, Inc.
Aldosterone Activates Vascular p38MAP Kinase and NADPH Oxidase Via c-Src
Glaucia E. Callera;
Rhian M. Touyz;
Rita C. Tostes;
Alvaro Yogi;
Ying He;
Sam Malkinson;
Ernesto L. Schiffrin
From CIHR Multidisciplinary Research Group on Hypertension (G.E.C., R.M.T., Y.H., S.M., E.L.S.), Clinical Research Institute of Montreal, University of Montreal, Canada; and the Department of Pharmacology (R.C.T., A.Y.), Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
Correspondence to Glaucia E. Callera, Clinical Research Institute of Montreal, 110 Pine Ave, West Montreal, Quebec H2W 1H7. E-mail callereg{at}ircm.qc.ca
Increasing evidence indicates that aldosterone elicits vascular effects through nongenomic signaling pathways. We tested the hypothesis that aldosterone induces activation of vascular mitogen-activated protein (MAP) kinases and NADPH oxidase via c-Src–dependent mechanisms in vascular smooth muscle cells (VSMCs). Aldosterone effects on activation of c-Src, p38MAP kinase, and NADPH oxidase, and incorporation of [3H]proline, an index of collagen synthesis, were assessed in cultured rat VSMCs. Studies were performed in the absence and presence of eplerenone, a selective mineralocorticoid receptor blocker, PP2, a selective Src inhibitor, and SB212190, a selective p38MAPK inhibitor. Phosphorylation of c-Src was dose-dependently increased by aldosterone, with maximal responses obtained at 10–7 mol/L. Aldosterone increased p38MAP kinase phosphorylation, NAD(P)H oxidase activation, and [3H]proline incorporation. These responses were abrogated by eplerenone and almost abolished by PP2. Aldosterone-stimulated incorporation of [3H]proline was significantly reduced by SB212190, indicating that p38MAP kinase plays a role in profibrotic actions of aldosterone. To unambiguously demonstrate the importance of aldosterone in c-Src signaling, VSMCs from c-Src+/+ and c-Src+/– mice were also studied. Aldosterone increased phosphorylation of c-Src, p38MAP kinase, and cortactin, a Src-specific substrate, in c-Src+/+ VSMCs, but not in c-Src-deficient cells. Taken together, our findings demonstrate that nongenomic signaling by aldosterone occurs through c-Src–dependent pathways. These processes may play an important role in profibrotic actions of aldosterone.
Key Words: aldosterone • mineralocorticoids • oxidative stress • vasculature • signal transduction • collagen
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