Abstract 13730: Cardiac-Specific GRK2 Ablation Can Promote Cardiac Myocyte Regeneration after Ischemia/Reperfusion Injury
Background G protein-coupled receptor kinase 2 (GRK2) is the most abundant GRK in the myocardium and has been shown to be a critical regulator of cardiac function at least in part de to regulation of β-adrenergic receptor (βAR) signaling. Studies from our lab show that silencing myocardial GRK2 expression in mice or preventing GRK2 activation with a peptide inhibitor (βARKct), can prevent or rescue heart failure progression after long term myocardial infarction and also lowering GRK2 expression and activity can protect against ischemic injury. Interestingly, there is a report that GRK2 can influence the cell cycle through expression of cyclin B and D. Accordingly, the objective of this study was to determine whether lowered myocyte GRK2 expression may improve cardiac outcomes after ischemia/reperfusion (I/R) injury due to improved cardiac repair through new myocyte formation or regenerative mechanisms.
Method and Results: We used cardiomyocyte-specific GRK2 knockout (GRK2KO) and also cardiac-specific GRK2 overexpressing (OE) mice along with non-transgenic control (NLC) mice and subjected them to sham or 30 min of myocardial ischemia via coronary artery ligation followed by 7 days of reperfusion. Cardiac function measured by echocardiography show that left ventricular internal diastolic diameter at diastole (LVID,d), ejection fraction (EF) and fraction shortening (FS) were significantly improved in GRK2KO group compared to NLC and GRK2OE mice. Consistently, the infarct size were also significantly less in GRK2KO (22.29±1.22%) than either NLC (33.11±0.95%) or GRK2OE (38.21±1.03%) mice. To determine whether GRK2 could influence new myocyte formation after I/R injury we injected 5-Bromo-2’-deoxy-uridine (BrdU, 0.04mg/g) before and after I/R and found significantly more BrdU positive cardiomyocytes in the infarct border zone of GRK2KO mice (0.0213±0.0088%) than that in GRK2OE (0.0020±0.0010%) and NLC (0.0030±0.0008%) mice. There was similar trend in remote area. This data indicate that GRK2 may be involved in the regulation of cardiac regeneration after cardiac ischemic damage.
Conclusion: Ablation of GRK2 in the heart may promote cardiomyocyte regeneration after ischemic injury and participate in the prevention of heart failure development.
- © 2011 by American Heart Association, Inc.