Rac1-Mediated Activation of Mineralocorticoid Receptor in Pressure Overload-Induced Cardiac Injury
Rac1-Mediated Activation of Mineralocorticoid Receptor in Pressure Overload-Induced Cardiac Injury
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DOI：
10.1161/hypertensionaha.115.06054
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发表时间：
2016-01-01
期刊：
影响因子：
8.3
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Ayuzawa, Nobuhiro;Nagase, Miki;Fujita, Toshiro
越来越多的证据表明，异常盐皮质激素受体（MR）激活在心力衰竭中起关键作用，临床研究显示MR阻断的有益作用。然而，心力衰竭时MR激活的机制仍不清楚。在这项研究中，我们观察到，小GTdR Rac 1有助于心肌MR激活，而Rac 1-MR通路激活导致心功能不全。横向主动脉缩窄引起的慢性压力超负荷小鼠心脏显示Rac 1激活和MR和MR靶基因表达的核积累增加，表明MR激活。药理学抑制Rac 1和Rac 1的杂合缺失在心肌细胞中抑制Rac 1诱导的MR信号传导，并减少NADPH氧化酶4基因诱导和活性氧的过度产生，从而减弱横向主动脉缩窄诱导的心脏肥大和功能障碍。因此，选择性MR拮抗剂依普利酮治疗阻断了横主动脉缩窄诱导的MR信号传导和NADPH氧化酶4基因上调，从而改善了心脏肥大和功能障碍。这些结果表明，Rac 1-MR通路的激活在心肌参与的发展压力负荷诱导的心力衰竭通过招聘的NADPH氧化酶的负责亚型。因此，心脏Rac 1-MR-NADPH氧化酶4途径可能是治疗压力超负荷心脏的治疗靶点。
There is increasing evidence for a crucial role of aberrant mineralocorticoid receptor (MR) activation in heart failure, with clinical studies showing beneficial effects of MR blockade. However, the mechanisms of MR activation in heart failure remain unclear. In this study, we observed that the small GTPase Rac1 contributes to myocardial MR activation, whereas Rac1-MR pathway activation leads to cardiac dysfunction. Mouse hearts subjected to chronic pressure overload induced by transverse aortic constriction showed Rac1 activation and increased nuclear accumulation of MR and expression of MR target genes, suggesting MR activation. Pharmacological inhibition of Rac1 and heterozygous deletion of Rac1 in cardiomyocytes suppressed Rac1-induced MR signaling and reduced NADPH oxidase 4 gene induction and reactive oxygen species overproduction, which attenuated transverse aortic constriction-induced cardiac hypertrophy and dysfunction. Consistently, treatment with the selective MR antagonist eplerenone blocked transverse aortic constriction-induced MR signaling and NADPH oxidase 4 gene upregulation, which improved cardiac hypertrophy and dysfunction. These findings suggest that Rac1-MR pathway activation in the myocardium is involved in development of heart failure induced by pressure load via recruitment of the responsible isoform of NADPH oxidase. Thus, the cardiac Rac1-MR-NADPH oxidase 4 pathway may be a therapeutic target for treatment of the pressure-overloaded heart.