Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases.
Myocardial pathology induced by aldosterone is dependent on non-canonical activities of G protein-coupled receptor kinases.
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DOI：
10.1038/ncomms10877
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发表时间：
2016-03-02
影响因子：
16.6
通讯作者：
Koch WJ
中科院分区：
文献类型：
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作者：
Cannavo A;Liccardo D;Eguchi A;Elliott KJ;Traynham CJ;Ibetti J;Eguchi S;Leosco D;Ferrara N;Rengo G;Koch WJ
高醛固酮增多症与心肌功能障碍有关，包括诱导心脏纤维化和适应性不良的肥厚。这些心脏毒性的机制还不完全清楚。在这里，我们发现由醛固酮激活的盐皮质激素受体(MR)通过线粒体G蛋白偶联受体激酶2(GRK2)的促死亡活性和GRK5促肥大作用而导致病理性心肌信号转导。此外，这些依赖MR的GRK2和GRK5非典型活动似乎涉及与血管紧张素II 1型受体(AT1R)的串扰。最重要的是，我们发现，在心脏GRK2基因敲除小鼠(KO)和GRK5基因敲除小鼠(GRK5 KO)中，由慢性高醛固酮症在体内引起的心功能障碍完全可以预防。然而，在GRK5KO小鼠中，醛固酮诱导的心肌肥厚是完全防止的。我们还显示了与影响GRK2水平的心力衰竭患者MR激活状态一致的人类数据。因此，我们的研究发现GRKs是改善与高醛固酮水平相关的病理心脏效应的靶点。高水平的醛固酮会导致心脏损害，而不是众所周知的对血压的影响。在这里，卡纳沃等人。研究表明，醛固酮介导的心脏病理涉及G蛋白偶联受体2(GRK2)和GRK5，它们整合了来自血管紧张素II受体(AT1R)的信号。
Hyper-aldosteronism is associated with myocardial dysfunction including induction of cardiac fibrosis and maladaptive hypertrophy. Mechanisms of these cardiotoxicities are not fully understood. Here we show that mineralocorticoid receptor (MR) activation by aldosterone leads to pathological myocardial signalling mediated by mitochondrial G protein-coupled receptor kinase 2 (GRK2) pro-death activity and GRK5 pro-hypertrophic action. Moreover, these MR-dependent GRK2 and GRK5 non-canonical activities appear to involve cross-talk with the angiotensin II type-1 receptor (AT1R). Most importantly, we show that ventricular dysfunction caused by chronic hyper-aldosteronism in vivo is completely prevented in cardiac Grk2 knockout mice (KO) and to a lesser extent in Grk5 KO mice. However, aldosterone-induced cardiac hypertrophy is totally prevented in Grk5 KO mice. We also show human data consistent with MR activation status in heart failure influencing GRK2 levels. Therefore, our study uncovers GRKs as targets for ameliorating pathological cardiac effects associated with high-aldosterone levels. High aldosterone levels cause heart damage independently of its well-known effect on blood pressure. Here, Cannavo et al. show that aldosterone-mediated cardiac pathology involves G protein-coupled receptor (GPCR) kinase 2 (GRK2) and GRK5 that integrate signals from angiotensin II receptor (AT1R).