Increased abundance of GRK2 [G protein-coupled receptor (GPCR) kinase 2] is associated with poor cardiac function in heart failure patients. In animal models, GRK2 contributes to the pathogenesis of heart failure after ischemia-reperfusion (IR) injury. In addition to its role in down-regulating activated GPCRs, GRK2 also localizes to mitochondria both basally and post-IR injury, where it regulates cellular metabolism. We previously showed that phosphorylation of GRK2 at Ser670 is essential for the translocation of GRK2 to the mitochondria of cardiomyocytes post-IR injury in vitro and that this localization promotes cell death. Here, we showed that mice with a S670A knock-in mutation in endogenous GRK2 showed reduced cardiomyocyte death and better cardiac function post-IR injury. Cultured GRK2-S670A knock-in cardiomyocytes subjected to IR in vitro showed enhanced glucose-mediated mitochondrial respiratory function that was partially due to maintenance of pyruvate dehydrogenase activity and improved glucose oxidation. Thus, we propose that mitochondrial GRK2 plays a detrimental role in cardiac glucose oxidation post-injury.

中文翻译：

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缺血后限制线粒体GRK2可通过减少心肌细胞死亡和维持葡萄糖氧化来赋予心脏保护作用。

心力衰竭患者中GRK2 [G蛋白偶联受体（GPCR）激酶2]丰度增加与心脏功能差有关。在动物模型中，GRK2有助于缺血再灌注（IR）损伤后心力衰竭的发病机理。除了在下调激活的GPCRs中的作用外，GRK2还在基础损伤和IR后损伤中定位于线粒体，在此调节细胞代谢。我们以前表明，Ser670处GRK2的磷酸化对于IR损伤后GRK2易位到心肌细胞的线粒体至关重要，并且这种定位会促进细胞死亡。在这里，我们显示了内源性GRK2中具有S670A敲入突变的小鼠显示出减少的心肌细胞死亡和更好的IR后心脏功能。培养的GRK2-S670A敲入体外心肌细胞显示出增强的葡萄糖介导的线粒体呼吸功能，这部分归因于丙酮酸脱氢酶活性的维持和葡萄糖氧化的改善。因此，我们建议线粒体GRK2在心脏葡萄糖氧化损伤后起有害作用。