Published Online
on September 12, 2005

A more recent version of this article appeared on October 1, 2005

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Submitted on April 27, 2005
Revised on May 17, 2005

c-Src-Dependent Nongenomic Signaling Responses to Aldosterone Are Increased in Vascular Myocytes From Spontaneously Hypertensive Rats

Glaucia E. Callera^*; Augusto C.I. Montezano; Alvaro Yogi; Rita C. Tostes; Ying He; Ernesto L. Schiffrin; and Rhian M. Touyz

From the Ottawa Health Research Institute (G.E.C., Y.H., R.M.T.), University of Ottawa, Ottawa, Canada; the CIHR Multidisciplinary Research Group on Hypertension (A.C.I.M., E.L.S., R.M.T.), Clinical Research Institute of Montreal, University of Montreal, Montreal, Canada; and the Department of Pharmacology (A.C.I.M., A.Y., R.C.T.), Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.

^* To whom correspondence should be addressed. E-mail: gcallera{at}uottawa.ca.

Abstract--Aldosterone plays an important role in the pathogenesis of hypertension. We previously demonstrated that nongenomic signaling by aldosterone in vascular smooth muscle cells occurs through c-Src-dependent pathways. Here we tested the hypothesis that upregulation of c-Src by aldosterone plays a role in increased mitogen-activated protein (MAP) kinase activation, [³H]-proline incorporation, and NADPH-driven generation of reactive oxygen species, thereby inducing cell growth, collagen production, and inflammation, respectively, in vascular smooth muscle cells from spontaneously hypertensive rats. The time course of c-Src phosphorylation by aldosterone was shifted to the left in vascular myocytes from hypertensive animals. Aldosterone rapidly increased phosphorylation of p38 MAP kinase and extracellular signal-regulated kinase with significantly greater effects in cells from spontaneously hypertensive rats versus control cells (P<0.05). Aldosterone increased NADPH oxidase activity with significantly greater responses in vascular smooth muscle cells from hypertensive animals (P<0.05). These events were associated with enhanced [³H]proline incorporation (index of collagen synthesis) in cells from spontaneously hypertensive rats (P<0.05). The NADPH oxidase activity increase, collagen synthesis, c-Src, and MAP kinase phosphorylation induced by aldosterone were significantly reduced by eplerenone (selective mineralocorticoid receptor blocker) and PP2 (selective c-Src inhibitor). In conclusion, nongenomic signaling by exogenous aldosterone, mediated through c-Src, is increased in vascular smooth muscle cells from spontaneously hypertensive rats. Upregulation of c-Src signaling may be important in the profibrotic and proinflammatory actions of aldosterone in this genetic model of hypertension.

Key words: aldosterone • signal transduction • rats, inbred SHR • oxidative stress • collagen

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