Aldosterone Stimulates the Cardiac Na+/H+ Exchanger via Transactivation of the Epidermal Growth Factor Receptor
Aldosterone Stimulates the Cardiac Na+/H+ Exchanger via Transactivation of the Epidermal Growth Factor Receptor
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DOI：
10.1161/hypertensionaha.111.176024
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发表时间：
2011-11-01
期刊：
影响因子：
8.3
通讯作者：
Aiello, Ernesto A.
中科院分区：
文献类型：
--
作者：
De Giusti, Veronica C.;Nolly, Mariela B.;Aiello, Ernesto A.
近年来，盐皮质激素受体拮抗剂在治疗心肌肥大和心力衰竭中的应用越来越重要。心脏Na +/H+交换器（NHE-1）上调诱导的醛固酮可以解释这些病理的发生。我们测试了醛固酮诱导的NHE-1刺激是否涉及表皮生长因子受体（EGFR）的反式激活。用荧光法测定大鼠心室肌细胞内pH值。醛固酮增强NHE-1活性。这种作用被螺内酯或依普利酮（盐皮质激素受体拮抗剂）取消，但不是由米非司酮（糖皮质激素受体拮抗剂）或放线菌酮（蛋白质合成抑制剂），表明该机制是由盐皮质激素受体介导的触发非基因组途径。醛固酮诱导的NHE-1刺激被EGFR激酶抑制剂AG1478消除，表明这是由EGFR的反式激活介导的。AG 1478也能阻断醛固酮诱导的激酶p90（RSK）和NHE-1丝氨酸703磷酸化水平的升高。外源性表皮生长因子模拟醛固酮对NHE-1活性的影响。表皮生长因子也能够增加活性氧的产生，并且表皮生长因子诱导的NHE-1的活化被活性氧清除剂N-2-巯基丙酰甘氨酸废除，表明活性氧作为信号分子参与了该机制。醛固酮通过EGFR的反式激活、活性氧物质的形成和交换剂的磷酸化来增强NHE-1活性。这些结果引起了人们对EGFR作为涉及醛固酮参与的心血管疾病的新的潜在治疗靶点的关注。（高血压。2011; 58：912 - 919.）。在线补充资料
The use of antagonists of the mineralocorticoid receptor in the treatment of myocardial hypertrophy and heart failure has gained increasing importance in the last years. The cardiac Na+/H+ exchanger (NHE-1) upregulation induced by aldosterone could account for the genesis of these pathologies. We tested whether aldosterone-induced NHE-1 stimulation involves the transactivation of the epidermal growth factor receptor (EGFR). Rat ventricular myocytes were used to measure intracellular pH with epifluorescence. Aldosterone enhanced the NHE-1 activity. This effect was canceled by spironolactone or eplerenone (mineralocorticoid receptor antagonists), but not by mifepristone (glucocorticoid receptor antagonist) or cycloheximide (protein synthesis inhibitor), indicating that the mechanism is mediated by the mineralocorticoid receptor triggering nongenomic pathways. Aldosterone-induced NHE-1 stimulation was abolished by the EGFR kinase inhibitor AG1478, suggesting that is mediated by transactivation of EGFR. The increase in the phosphorylation level of the kinase p90(RSK) and NHE-1 serine703 induced by aldosterone was also blocked by AG1478. Exogenous epidermal growth factor mimicked the effects of aldosterone on NHE-1 activity. Epidermal growth factor was also able to increase reactive oxygen species production, and the epidermal growth factor-induced activation of the NHE-1 was abrogated by the reactive oxygen species scavenger N-2-mercaptopropionyl glycine, indicating that reactive oxygen species are participating as signaling molecules in this mechanism. Aldosterone enhances the NHE-1 activity via transactivation of the EGFR, formation of reactive oxygen species, and phosphorylation of the exchanger. These results call attention to the consideration of the EGFR as a new potential therapeutic target of the cardiovascular pathologies involving the participation of aldosterone. (Hypertension. 2011; 58: 912-919.). Online Data Supplement