The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
The signaling pathway for aldosterone-induced mitochondrial production of superoxide anion in the myocardium
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DOI：
10.1016/j.yjmcc.2013.12.004
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发表时间：
2014-02-01
影响因子：
5
通讯作者：
Ennis, I. L.
中科院分区：
文献类型：
--
作者：
Nolly, M. B.;Caldiz, C. I.;Ennis, I. L.
盐皮质激素受体（MR）拮抗剂可降低氧化应激常见的心力衰竭患者的发病率和死亡率;然而，这种保护作用的潜在机制尚不清楚。由于醛固酮刺激活性氧（ROS）的产生在几个组织中，我们探讨了其作用和细胞内途径参与大鼠心肌。醛固酮剂量依赖性地增加心肌切片中O-2（-）的产生。在10 nmol/L时，醛固酮使O-2（-）增加到对照组的165 8.8%，这种作用不仅被MR拮抗剂依普利酮和螺内酯（分别为107 +/- 7.8和103 +/-5.3%）阻止，而且被EGF受体（EGFR）拮抗剂AG 1478（105 +/- 8.0%）阻止。通过直接心肌内注射编码针对MR的SiRNA的慢病毒来沉默MR表达，也获得了类似的结果。mK（ATP）通道开放剂二氮嗪模拟了醛固酮对O-2（-）产生的作用，并通过阻止其开放来阻断。5-HD和格列本脲，暗示线粒体是O-2（-）的来源。用鱼藤酮抑制呼吸链或用环孢霉素A或邦格列酸抑制线粒体通透性转换（MPT）也可消除醛固酮诱导的O-2（-）产生。此外，醛固酮的作用依赖于NADPH氧化酶和磷酸肌醇3-激酶的激活，夹竹桃黄素和渥曼青霉素分别抑制它。EGF（0.1 μ g/ mL）同样增加O-2（-），虽然在这种情况下MR拮抗剂没有效果，这表明EGFR反式激活发生在MR激活的下游。抑制mK（ATP）通道、呼吸链或MPT并不能阻止Akt磷酸化，支持它发生在线粒体上游。重要的是，心肌细胞被证实为醛固酮诱导的线粒体ROS生产在分离的心肌细胞中进行的实验中的来源，这些结果使我们能够推测，在心力衰竭的有益效果的MR拮抗剂可能与减少氧化应激。(C)2013爱思唯尔有限公司保留所有权利。
Mineralocorticoid receptor (MR) antagonists decrease morbidity and mortality in heart failure patients for whom oxidative stress is usual; however, the underlying mechanism for this protection is unclear. Since aldosterone stimulates reactive oxygen species (ROS) production in several tissues, we explored its effect and the intracellular pathway involved in the rat myocardium. Aldosterone dose-dependently increased O-2(-) production in myocardial slices. At 10 nmol/L, aldosterone increased O-2(-) to 165 8.8% of control, an effect prevented not only by the MR antagonists eplerenone and spironolactone (107 +/- 7.8 and 103 +/- 5.3%, respectively) but also by AG1478 (105 +/- 8.0%), antagonist of the EGF receptor (EGFR). Similar results were obtained by silencing MR expression through the direct intramyocardial injection of a lentivirus coding for a siRNA against the MR The aldosterone effect on O-2(-) production was mimicked by the mK(ATP) channel opener diazoxide and blocked by preventing its opening with 5-HD and glibenclamide, implicating the mitochondria as the source of O-2(-). Inhibiting the respiratory chain with rotenone or mitochondrial permeability transition (MPT) with cyclosporine A or bongkrekic acid also canceled aldosterone-induced O-2(-) production. In addition, aldosterone effect depended on NADPH oxidase and phosphoinositide 3-kinase activation, as apocynin and wortmannin, respectively, inhibited it. EGF (0.1 mu g/ mL) similarly increased O-2(-) , although in this case MR antagonists had no effect, suggesting that EGFR transactivation occurred downstream from MR activation. Inhibition of mK(ATP) channels, the respiratory chain, or MPT did not prevent Akt phosphorylation, supporting that it happened upstream of the mitochondria. Importantly, cardiomyocytes were confirmed as a source of aldosterone induced mitochondrial ROS production in experiments performed in isolated cardiac myocytes.These results allow us to speculate that the beneficial effects of MR antagonists in heart failure may be related to a decrease in oxidative stress. (C) 2013 Elsevier Ltd. All rights reserved.