Abstract 3392: G Protein-Coupled Receptor Kinase 2 Ablation in Cardiac Myocytes Decreases Ischemia/Reperfusion Induced Myocardial Apoptosis and Improves Cardiac Function
Objective: Previous studies by us have been shown that silencing of myocardial G protein-coupled receptor kinase 2 (GRK2) expression in mice can prevent heart failure progression after myocardial infarction. In this study, we wanted to determine whether acute cardiac effects with lower GRK2 may be a contributing mechanism and investigated apoptotic responses after ischemia/reperfusion (I/R) injury.
Methods: Mice with inducible cardiomyocyte ablation of the GRK2 gene were generated using our floxed GRK2 mice bred with MerCreMer (MCM) mice. After tamoxifin treatment, control MCM mice along with α-MHC-MerCreMer×GRK2 fl/fl (GRK2 KO) mice were subjected to 30 min myocardial ischemia and 24 h reperfusion. After 24 h reperfusion, cardiac function was analyzed via echocardiography and hemodynamic measurement. Cardiac infarct size (using TTC staining), tissue apoptosis (TUNEL staining and Caspase-3 activity) as well as GRK2 expression were analyzed.
Results: Tamoxifin treatment inhibits GRK2 expression. Results from Echo and hemodynamic measurements show a trend for improved post-I/R cardiac function in GRK2 KO mice. More importantly, LV infarct size was significantly decreased in GRK2 KO mice compared to control. Additionally, myocardial apoptotic ratio was also decreased in GRK2 KO mice with less GRK2 expression (MCM 20.19±1.45 vs GRK2 KO 13.78±1.12, n=5, P<0.01).
Conclusion: Loss of GRK2 expression limits myocardial damage after ischemic injury presumably by decreased myocyte apoptosis, which leads to improved functional recovery acutely, which may contribute to the chronic benefits in heart failure with GRK2 targeted inhibition.