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(Hypertension. 2005;46:1032.)
© 2005 American Heart Association, Inc.

Part 2 Original Articles

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; 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.

Correspondence to Glaucia E. Callera, Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Health Sciences Bldg, Room 1333A, 451 Smyth Rd, Ottawa, Ontario K1H 8M5, Canada. E-mail gcallera{at}uottawa.ca

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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