Aldosterone Signaling Associates With p300/GATA4 Transcriptional Pathway During the Hypertrophic Response of Cardiomyocytes
Aldosterone Signaling Associates With p300/GATA4 Transcriptional Pathway During the Hypertrophic Response of Cardiomyocytes
复制标题
DOI：
10.1253/circj.cj-09-0050
复制
发表时间：
2010-01-01
影响因子：
3.3
通讯作者：
Hasegawa, Koji
中科院分区：
文献类型：
--
作者：
Yoshida, Yoshinori;Morimoto, Tatsuya;Hasegawa, Koji
背景：醛固酮通过结合特定的矿物皮质激素受体（MRs）发挥作用。螺内酯阻断醛固酮系统，可改善人类心力衰竭，但MR阻断的确切分子机制尚不清楚。方法和结果：用苯肾上腺素（PE）、醛固酮和/或螺内酯刺激新生大鼠心肌细胞。研究了MR与p300的关联，p300是增生性反应所需的GATA4的转录辅激活因子。MR和p300协同激活gata4依赖性房钠因子（ANF）启动子活性。用PE刺激心肌细胞诱导MRs易位进入细胞核，并显著增加MRs与p300的相关性。与MR和p300的协同激活相一致，醛固酮进一步增强了pe诱导的细胞大小增加和ANF基因转录的诱导。螺内酯阻断MR激活可抑制pe诱导的MR核易位和肥大反应。结论：研究首次证实，醛固酮/MR系统在心肌细胞肥厚反应过程中与p300/GATA4转录通路相关，这可能为醛固酮阻断剂在人类心力衰竭治疗中的有益作用提供了一种机制。（cirj 2010; 74: 156-162）
Background: Aldosterone exerts its effect by binding to specific mineralocorticoid receptors (MRs). Spironolactone blocks the aldosterone system, which ameliorates heart failure in humans, but the precise molecular mechanisms of MR blockade are unclear.Methods and Results: Neonatal rat cardiomyocytes were stimulated with phenylephrine (PE), aldosterone, and/or spironolactone. The association of the MR with p300, a transcriptional coactivator of GATA4 required for hypertrophic responses, was examined. MR and p300 synergistically activated GATA4-dependent atrial natriuretic factor (ANF) promoter activities. The stimulation of cardiomyocytes with PE induced translocation of the MRs into the nuclei and markedly increased the association of MRs with p300. Compatible with the synergistic activation by the MR and p300, aldosterone further augmented the PE-induced increase in cell size and induction of ANF gene transcription. Blockade of MR activation by spironolactone inhibited the PE-induced nuclear translocation of MRs and hypertrophic responses.Conclusions: For the first time it has been demonstrated that the aldosterone/MR system associates with the p300/GATA4 transcriptional pathway during the hypertrophic response of cardiomyocytes, and may provide a mechanism of the beneficial effects of aldosterone-blocking agents in heart failure therapy in humans. (Circ J 2010; 74: 156-162)