G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism.
G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism.
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DOI：
10.1161/circresaha.114.300513
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发表时间：
2014-05-09
影响因子：
20.1
通讯作者：
Koch WJ
中科院分区：
文献类型：
--
作者：
Woodall MC;Ciccarelli M;Woodall BP;Koch WJ
心力衰竭（HF）给全球医疗保健系统造成巨大负担，影响超过2300万人。有许多心血管疾病导致HF的发展，多种风险因素加速其发生，但无论其根本原因如何，HF的特征是心肌收缩力显著降低和泵功能丧失。在人HF和几种动物模型中一致显示上调的一种生物标志物分子是G蛋白偶联受体（GPCR）激酶2（GRK 2），这是一种最初发现参与GPCR脱敏的激酶，尤其是β-肾上腺素能受体（β AR）。事实上，较高水平的GRK 2可损害β AR介导的正性肌力储备，并且其抑制或分子减少已显示在几种动物模型（包括HF的临床前猪模型）中改善泵功能。最近，已经描述了GRK 2在心血管疾病中的非经典作用，包括胰岛素信号传导的负调节，在肌细胞存活和凋亡信号传导中的作用，并且已经显示其定位于线粒体中/线粒体上。GRK 2的这些新作用表明GRK 2可能是肌细胞中的节点连接，影响心脏收缩功能和细胞代谢和存活，并独立于其对GPCR脱敏的典型作用而促成HF。在这篇综述中，GRK 2的经典和非经典的角色将进行讨论，重点是最近发现的GRK 2在心肌细胞代谢中的作用，以及这些作用可能对心肌收缩功能和HF发展的影响。
Heart failure (HF) causes a tremendous burden on the worldwide healthcare system, affecting more than 23 million people. There are many cardiovascular disorders that contribute to the development of HF and multiple risk factors that accelerate its occurrence, but regardless of its underlying cause, HF is characterized by a marked decrease in myocardial contractility and loss of pump function. One biomarker molecule consistently shown to be upregulated in human HF and several animal models is G protein-coupled receptor (GPCR) kinase 2 (GRK2), a kinase originally discovered to be involved in GPCR desensitization, especially β-adrenergic receptors (βARs). Indeed, higher levels of GRK2 can impair βAR-mediated inotropic reserve and its inhibition or molecular reduction has shown to improve pump function in several animal models including a pre-clinical pig model of HF. Recently, non-classical roles for GRK2 in cardiovascular disease have been described, including negative regulation of insulin signaling, a role in myocyte cell survival and apoptotic signaling, and it has been shown to be localized in/on mitochondria. These new roles of GRK2 suggest that GRK2 may be a nodal link in the myocyte, influencing both cardiac contractile function and cell metabolism and survival and contributing to HF independent of its canonical role on GPCR desensitization. In this review, classical and non-classical roles for GRK2 will be discussed, focusing on recently discovered roles for GRK2 in cardiomyocyte metabolism and the effects that these roles may have on myocardial contractile function and HF development.