Ikeda U, Hyman R, Smith T W, Medford R M
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
J Biol Chem. 1991 Jun 25;266(18):12058-66.
By altering the Na+/K+ electrochemical gradient, Na+,K(+)-ATPase activity profoundly influences cardiac cell excitability and contractility. The recent finding of mineralocorticoid hormone receptors in the heart implies that Na+,K(+)-ATPase gene expression, and hence cardiac function, is regulated by aldosterone, a corticosteroid hormone associated with certain forms of hypertension and classically involved in regulating Na+,K(+)-ATPase gene expression and transepithelial Na+ transport in tissues such as the kidney. The regulation by aldosterone of the major cardiac Na+,K(+)-ATPase isoform genes, alpha-1 and beta-1, were studied in adult and neonatal rat ventricular cardiocytes grown in defined serum-free media. In both cell types, aldosterone-induced a rapid and sustained 3-fold induction in alpha-1 mRNA accumulation within 6 h. beta-1 mRNA was similarly induced. alpha-1 mRNA induction occurred over the physiological range with an EC50 of 1-2 nM, consistent with binding of aldosterone to the high affinity mineralocorticoid hormone receptor. In adult cardiocytes, this was associated with a 36% increase in alpha subunit protein accumulation and an increase in Na(+)-K(+)-ATPase transport activity. Aldosterone did not alter the 3-h half-life of alpha-1 mRNA, indicating an induction of alpha-1 mRNA synthesis. Aldosterone-dependent alpha-1 mRNA accumulation was not blocked by the protein synthesis inhibitor cycloheximide, whereas amiloride inhibited both an aldosterone-dependent increase in intracellular Na+ [Na+]i) and alpha-1 mRNA accumulation. This demonstrates that aldosterone directly stimulates Na+,K(+)-ATPase alpha-1 subunit mRNA synthesis and protein accumulation in cardiac cells throughout development and suggests that the heart is a mineralocorticoid-responsive organ. An early increase in [Na+]i may be a proximal event in the mediation of the hormone effect.
通过改变钠钾电化学梯度，钠钾ATP酶活性深刻影响心脏细胞的兴奋性和收缩性。近期在心脏中发现盐皮质激素受体意味着钠钾ATP酶基因表达以及心脏功能受醛固酮调节，醛固酮是一种皮质类固醇激素，与某些形式的高血压相关，并且传统上参与调节肾脏等组织中的钠钾ATP酶基因表达和跨上皮钠转运。在限定的无血清培养基中培养的成年和新生大鼠心室心肌细胞中，研究了醛固酮对主要心脏钠钾ATP酶同工型基因α-1和β-1的调节作用。在这两种细胞类型中，醛固酮在6小时内诱导α-1 mRNA积累迅速且持续增加3倍。β-1 mRNA也有类似诱导。α-1 mRNA诱导在生理范围内发生，EC50为1-2 nM，这与醛固酮与高亲和力盐皮质激素受体的结合一致。在成年心肌细胞中，这与α亚基蛋白积累增加36%以及钠钾ATP酶转运活性增加有关。醛固酮并未改变α-1 mRNA的3小时半衰期，表明诱导了α-1 mRNA合成。醛固酮依赖性α-1 mRNA积累未被蛋白质合成抑制剂环己酰亚胺阻断，而氨氯吡咪抑制了醛固酮依赖性细胞内钠浓度（[Na+]i）增加以及α-1 mRNA积累。这表明醛固酮在整个发育过程中直接刺激心脏细胞中钠钾ATP酶α-1亚基mRNA合成和蛋白质积累，并提示心脏是一个盐皮质激素反应性器官。细胞内钠浓度（[Na+]i）的早期增加可能是激素效应介导中的近端事件。
