GRK2 as a novel gene therapy target in heart failure.
GRK2 as a novel gene therapy target in heart failure.
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DOI：
10.1016/j.yjmcc.2010.08.014
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发表时间：
2011-05
影响因子：
5
通讯作者：
Koch WJ
中科院分区：
文献类型：
--
作者：
Rengo G;Lymperopoulos A;Leosco D;Koch WJ
尽管在药理学和临床治疗方面取得了重大进展，但心力衰竭（HF）仍然是世界范围内发病率和死亡率的主要原因。心衰是一种慢性进行性临床综合征，以左心室射血分数降低和心肌不良重构为特征。在过去几年中，利用动物模型揭示心衰发病和进展的细胞和分子机制取得了显著进展。这些研究揭示了潜在的新的治疗靶点/策略。心脏基因转移的应用，允许在心肌细胞靶点的操作，似乎是一个有前途的治疗工具在心衰。β-肾上腺素能受体（βAR）功能障碍是慢性心衰的标志性异常，G蛋白偶联受体激酶2 （GRK2）水平/活性升高是这些改变之一。在过去的15年中，一些动物研究表明，GRK2肽抑制剂（βARKct）的表达可以改善衰竭心肌的收缩功能，包括促进左室的反向重构。因此，数据支持βARKct作为人类心衰治疗应用的有希望的候选物。重要的是，最近对心脏特异性GRK2敲除小鼠的研究证实了GRK2在衰竭的肌细胞中是病理性的。本综述的目的是讨论：1)HF中βAR信号的改变，2)GRK2操作对衰竭心肌影响的转基因小鼠研究证据，3)体内βARKct基因治疗HF的治疗效果，以及4)通过抑制肾上腺GRK2活性降低HF相关交感神经系统亢进的可能性。
Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains a leading cause of morbidity and mortality worldwide. HF is a chronic and progressive clinical syndrome characterized by a reduction in left ventricular (LV) ejection fraction and adverse remodeling of the myocardium. The past several years have seen remarkable progress using animal models in unravelling the cellular and molecular mechanisms underlying HF pathogenesis and progression. These studies have revealed potentially novel therapeutic targets/strategies. The application of cardiac gene transfer, which allows for the manipulation of targets in cardiomyocytes, appears to be a promising therapeutic tool in HF. β-adrenergic receptor (βAR) dysfunction represents a hallmark abnormality of chronic HF, and increased G protein-coupled receptor kinase 2 (GRK2) levels/activity in failing myocardium is among these alterations. In the past 15 years, several animal studies have shown that expression of a peptide inhibitor of GRK2 (βARKct) can improve the contractile function of failing myocardium including promoting reverse remodeling of the LV. Therefore, data support the use of the βARKct as a promising candidate for therapeutic application in human HF. Importantly, recent studies in cardiac-specific GRK2 knockout mice have corroborated GRK2 being pathological in failing myocytes. The purpose of this review is to discuss: 1) the alterations of βAR signalling that occur in HF, 2) the evidence from transgenic mouse studies investigating the impact of GRK2 manipulation in failing myocardium, 3) the therapeutic efficacy of in vivo βARKct gene therapy in HF, and 4) the intriguing possibility of lowering HF-related sympathetic nervous system hyperactivity by inhibiting GRK2 activity in the adrenal gland.