Aldosterone modulates If current through gene expression in cultured neonatal rat ventricular myocytes
Aldosterone modulates If current through gene expression in cultured neonatal rat ventricular myocytes
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DOI：
10.1152/ajpheart.01399.2006
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发表时间：
2007-11-01
影响因子：
4.8
通讯作者：
Yasui, Kenji
中科院分区：
文献类型：
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作者：
Muto, Takao;Ueda, Norihiro;Yasui, Kenji
盐皮质激素受体 (MR) 拮抗剂可降低心力衰竭患者心源性猝死的发生率，正如两项临床试验（随机醛内酯评估研究和依普利酮急性心肌梗死后心力衰竭疗效和生存研究）所报告的那样。醛固酮已被证明可以通过改变各种离子通道的表达或功能来增加心律失常的倾向。在本研究中，我们利用全细胞膜片钳技术、实时PCR和蛋白质印迹研究了醛固酮对培养的新生大鼠心室肌细胞中超极化激活电流（I-f）通道表达的影响。与 10 nM 醛固酮一起孵育 17-24 小时可通过增加舒张期去极化来显着加快自发搏动的速率。由 -50 至 -130 mV 的超极化引起的 I-f 电流使醛固酮显着增加 10 nM（1.9 倍）。暴露于醛固酮 1.5 小时，超极化激活的环核苷酸门控 (HCN) 2 mRNA 增加 26.3%，HCN4 mRNA 增加 47.2%，而 HCN1 mRNA 表达不受影响。醛固酮（孵育 24 小时）会增加 HCN2 蛋白（增加 60.0%）和 HCN4 蛋白（增加 84.8%）的表达，但不会增加 HCN1 蛋白的表达。 MR拮抗剂（1μM依普利酮或0.1μM螺内酯）消除了10nM醛固酮增加的I-f通道表达（电流、mRNA和蛋白质水平）。相反，1μM醛固酮下调I-f通道基因表达。糖皮质激素受体拮抗剂 (100 nM RU-38486) 不会影响 10 nM 醛固酮的 I-f 电流增加。这些发现表明，生理浓度的醛固酮通过心肌细胞中的 MR 激活上调 I-f 通道基因表达，并可能增加兴奋性，这在病理生理条件下可能具有潜在的致心律失常作用。
Mineralocorticoid receptor (MR) antagonists decrease the incidence of sudden cardiac death in patients with heart failure, as has been reported in two clinical trials (Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). Aldosterone has been shown to increase the propensity to arrhythmias by changing the expression or function of various ion channels. In this study, we investigate the effect of aldosterone on the expression of hyperpolarization-activated current (I-f) channels in cultured neonatal rat ventricular myocytes, using the whole cell patch-clamp technique, real-time PCR, and Western blotting. Incubation with 10 nM aldosterone for 17-24 h significantly accelerates the rate of spontaneous beating by increasing diastolic depolarization. I-f current elicited by hyperpolarization from -50 to -130 mV significantly increases aldosterone by 10 nM (by 1.9-fold). Exposure to aldosterone for 1.5 h increases hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 mRNA by 26.3% and HCN4 mRNA by 47.2%, whereas HCN1 mRNA expression remains unaffected. Aldosterone (24-h incubation) increases the expression of HCN2 protein (by 60.0%) and HCN4 protein (by 84.8%), but not HCN1 protein. MR antagonists (1 mu M eplerenone or 0.1 mu M spironolactone) abolish the increase of I-f channel expression ( currents, mRNA, and protein levels) by 10 nM aldosterone. In contrast, 1 mu M aldosterone downregulated I-f channel gene expression. Glucocorticoid receptor antagonist (100 nM RU-38486) did not affect the increase of I-f current by 10 nM aldosterone. These findings suggest that aldosterone in physiological concentrations upregulates I-f channel gene expression by MR activation in cardiac myocytes and may increase excitability, which may have a potential proarrhythmic bearing under pathophysiological conditions.