c-Src-dependent nongenomic signaling responses to aldosterone are increased in vascular myocytes from spontaneously hypertensive rats

被引:89
作者
Callera, GE
Montezano, ACI
Yogi, A
Tostes, RC
He, Y
Schiffrin, EL
Touyz, RM
机构
[1] Univ Ottawa, Ottawa Hlth Res Inst, Kidney Res Ctr, Ottawa, ON K1H 8M5, Canada
[2] Univ Montreal, Clin Res Inst Montreal, CIHR Multidisciplinary Res Grp Hypertens, Montreal, PQ, Canada
[3] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo, Brazil
关键词
aldosterone; signal transduction; rats; inbred SHR; oxidative stress; collagen;
D O I
10.1161/01.HYP.0000176588.51027.35
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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, [H-3]-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 [H-3]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.
引用
收藏
页码:1032 / 1038
页数:7
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