Abstract 15: Limiting GRK2 in the Ischemic Heart can Promote Cardiac Regeneration
The detrimental role of G protein-coupled receptor (GPCR) kinase (GRK2) following cardiac injury/stress has been documented over the last two decades. Importantly, our lab has shown that inhibition or deletion of GRK2 in cardiomyocytes can prevent and also rescue heart failure (HF) phenotypes. Its role in GPCR desensitization including regulation of β-adrenergic receptors (βARs) during HF development has been well characterized. However, recently our lab and others have found that GRK2 can have novel GPCR-independent effects in the heart that appear to contribute to its pathological effects and thus, inhibition of these actions of GRK2 may contribute to therapeutic effects seen. In this study we explored whether the cardiac repair observed with lower myocardial GRK2 might involve regenerative processes. In cardiac-specific GRK2 knockout (KO) mice and also transgenic mice with cardiac-targeted expression of the βARKct, a peptide inhibitor of GRK2 activation via Gβγ sequestration, we induced HF via coronary artery ligation and subsequent myocardial infarction (MI) and measured aspects of cardiac repair including potential regeneration indices. Post-MI mice (GRK2 KO, βARKct mice and wild-type and non-transgenic control mice) were treated with 5-ethynyl-2’-deoxyuridine (EdU) or Bromodeoxyuridine (BrDU) to examine indices of DNA proliferation in myocytes as well as Ki67 staining. We also quantitated c-kit+ cells and myocytes in the post-MI hearts to compare how either loss of GRK2 expression or inhibition via its C-terminus altered potential regeneration mechanisms compared to control mice with endogenous GRK2 levels and activity. We found significantly more BrDU positive myocytes in post-MI hearts with lower GRK2 and this correlated with increased myocytes that were also cKit+. Thus, it appears that the myocardial functional improvement seen in the post-MI heart with targeted lowering of GRK2 involves, to at least a certain extent, regenerative mechanisms. This adds novel insight into the therapeutic potential of GRK2 inhibition for HF.
Author Disclosures: M. Scimia: None L. Zuo: None K.E. Sydnes: None D.A. Zuppo: None E. Gao: None W.J. Koch: None.
- © 2014 by American Heart Association, Inc.