Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation
| Autor: | Meryl C. Woodall, J. Kurt Chuprun, Erhe Gao, Konstantinos Drosatos, Brett R. Brown, Priscila Y. Sato, Jessica Ibetti, Anna Maria Lucchese, Ancai Yuan, Rajika Roy, Walter J. Koch, Doug G. Tilley, Laurel A. Grisanti, Christopher J. Traynham |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Programmed cell death G-Protein-Coupled Receptor Kinase 2 Apoptosis Mitochondrion Biochemistry Article 03 medical and health sciences Mice Oxygen Consumption Ischemia Serine Myocyte Animals Point Mutation Respiratory function Myocytes Cardiac Phosphorylation Molecular Biology Cardioprotection Heart Failure Alanine biology Chemistry Kinase Beta adrenergic receptor kinase Cell Biology Cell biology Mitochondria 030104 developmental biology Glucose biology.protein Signal transduction Oxidation-Reduction Signal Transduction |
| Zdroj: | Science signaling. 11(560) |
| ISSN: | 1937-9145 |
| Popis: | 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 Ser(670) 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. |
| Databáze: | OpenAIRE |
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