Restricting mitochondrial GRK2 post-ischemia confers cardioprotection by reducing myocyte death and maintaining glucose oxidation.pdf
Priscila Y. Sato
J. Kurt Chuprun
Laurel A. Grisanti
Meryl C. Woodall
Brett R. Brown
Rajika Roy
Christopher J. Traynham
Jessica Ibetti
Anna M. Lucchese
Ancai Yuan
Konstantinos Drostatos
Douglas G. Tilley
Erhe Gao
Walter J. Koch
10.25376/hra.7819961.v1
https://hra.figshare.com/articles/journal_contribution/Restricting_mitochondrial_GRK2_post-ischemia_confers_cardioprotection_by_reducing_myocyte_death_and_maintaining_glucose_oxidation_pdf/7819961
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.
2019-03-08 13:51:25
GRK2
Mitochondria
Ischemia/Reperfusion Injury
Heart
Cardiology (incl. Cardiovascular Diseases)