Abstract 103: Cardiac Grk2 Blockade Augments β2-Adrenergic Receptor-Dependent Contractility and Survival Post Myocardial Infarction
ß1- and ß2-adrenergic receptors (ßARs) are G-protein coupled receptors (GPCRs) that play clearly distinct roles in cardiac physiology/pathology: cardiomyocyte contraction is readily stimulated by ß1AR but not ß2AR signaling, and ß1AR signaling is largely pro-apoptotic in the heart, in contrast to the cardioprotective ß2AR signaling. These differences might be due to assembly of different macromolecular complexes containing phosphodiesterases (PDEs), which constrain pro-contractile 3'-5'-adenosine monophosphate (cAMP) signaling. Additionally, ß2AR is readily phosphorylated by GPCR kinase (GRK)-2, which then recruits ß-arrestin (ßarr), a universal GPCR adapter/scaffolding molecule, to the receptor. ßarrs reduce ß2AR pro-contractile signaling by desensitizing the receptor and can either increase or decrease apoptosis via interactions with several downstream effectors. Herein, we sought to investigate the effect of ßarr recruitment blockade on ß2AR-dependent contractility and survival in vivo. To this end, we crossed ß1AR knockout (B1KO) mice, lacking the ß1AR, with M27 mice, which overexpress, specifically in cardiac myocytes, the GRK2 inhibitor GRK2ct (or ßARKct). By blocking GRK2-mediated phosphorylation, ßarr binding to ß2AR is prevented. We studied the offspring both under normal conditions and after surgically induced myocardial infarction (MI). Contractility was significantly augmented in M27/B1KO mice compared to control B1KO's, both in healthy mice (ejection fraction (EF): 69+1.8% vs. 57+1.7%, respectively, p<0.05, n=8) and at 4 weeks post-MI (EF: 42.6+0.1% vs. 25+3.9%, respectively, p<0.05, n=8). In addition, M27/B1KO mice exhibited less cardiac dilatation, increased survival and decreased cardiac apoptosis and infarct size, compared to B1KO's, at 4 weeks post-MI. At the molecular level, M27/B1KO hearts displayed significantly less membrane recruitment of PDEs, upregulation of the anti-apoptotic Bcl-2 and a more favorable inflammatory cytokine profile vs. B1KO hearts. Thus, cardiac GRK2 inhibition by GRK2ct increases both ß2AR-dependent contractility and survival in post-MI heart failure and could be pursued in situations where ß2AR agonism is beneficial, e.g. in patients awaiting cardiac transplantation.
- © 2012 by American Heart Association, Inc.