Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation.
Sci Signal
; 11(560)2018 12 11.
Article
de En
| MEDLINE
| ID: mdl-30538174
ABSTRACT
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Apoptose
/
Myocytes cardiaques
/
Kinase-2 associée au récepteur couplé à une protéine G
/
Glucose
/
Défaillance cardiaque
/
Ischémie
/
Mitochondries
Limites:
Animals
Langue:
En
Journal:
Sci Signal
Sujet du journal:
CIENCIA
/
FISIOLOGIA
Année:
2018
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique