Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src
Aldosterone activates vascular p38MAP kinase and NADPH oxidase via c-Src
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DOI：
10.1161/01.hyp.0000154365.30593.d3
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发表时间：
2005-04-01
期刊：
影响因子：
8.3
通讯作者：
Schiffrin, EL
中科院分区：
文献类型：
--
作者：
Callera, GE;Touyz, RM;Schiffrin, EL
越来越多的证据表明，醛固酮通过非基因组信号通路发挥血管效应。我们检验了醛固酮通过c-Src依赖性机制诱导血管平滑肌细胞（VSMCs）中血管丝裂原活化蛋白（MAP）激酶和NADPH氧化酶活化的假设。醛固酮对c-Src，p38 MAP激酶和NADPH氧化酶的激活，以及[H-3]脯氨酸的掺入，胶原合成的指数，在培养的大鼠VSMCs进行了评估。在不存在和存在依普利酮（一种选择性盐皮质激素受体阻断剂）、PP 2（一种选择性Src抑制剂）和SB 212190（一种选择性p38 MAPK抑制剂）的情况下进行研究。醛固酮可剂量依赖性地增加c-Src的磷酸化，在10（-7）mol/L时达到最大反应。醛固酮增加p38 MAP激酶磷酸化、NAD（P）H氧化酶活性和[H-3]脯氨酸掺入。这些反应被依普利酮废除，几乎被PP 2废除。醛固酮刺激的[H-3]脯氨酸掺入显着减少SB 212190，表明p38 MAP激酶在醛固酮的促纤维化作用中起作用。为了明确证明醛固酮在c-Src信号传导中的重要性，还研究了来自c-Src（+/+）和c-Src（+/-）小鼠的VSMC。在c-Src（+/+）VSMCs中，醛固酮增加c-Src、p38 MAP激酶和corneum（一种Src特异性底物）的磷酸化，但在c-Src缺陷细胞中不增加。总之，我们的研究结果表明，醛固酮的非基因组信号传导通过c-Src依赖性途径发生。这些过程可能在醛固酮的促纤维化作用中起重要作用。
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 [H-3]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 [H-3]proline incorporation. These responses were abrogated by eplerenone and almost abolished by PP2. Aldosterone-stimulated incorporation of [H-3]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.