| First Author | Brinks H | Year | 2010 |
| Journal | Circ Res | Volume | 107 |
| Issue | 9 | Pages | 1140-9 |
| PubMed ID | 20814022 | Mgi Jnum | J:178191 |
| Mgi Id | MGI:5297661 | Doi | 10.1161/CIRCRESAHA.110.221010 |
| Citation | Brinks H, et al. (2010) Level of G protein-coupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms. Circ Res 107(9):1140-9 |
| abstractText | RATIONALE: Activation of prosurvival kinases and subsequent nitric oxide (NO) production by certain G protein-coupled receptors (GPCRs) protects myocardium in ischemia/reperfusion injury (I/R) models. GPCR signaling pathways are regulated by GPCR kinases (GRKs), and GRK2 has been shown to be a critical molecule in normal and pathological cardiac function. OBJECTIVE: A loss of cardiac GRK2 activity is known to arrest progression of heart failure (HF), at least in part by normalization of cardiac beta-adrenergic receptor (betaAR) signaling. Chronic HF studies have been performed with GRK2 knockout mice, as well as expression of the betaARKct, a peptide inhibitor of GRK2 activity. This study was conducted to examine the role of GRK2 and its activity during acute myocardial ischemic injury using an I/R model. METHODS AND RESULTS: We demonstrate, using cardiac-specific GRK2 and betaARKct-expressing transgenic mice, a deleterious effect of GRK2 on in vivo myocardial I/R injury with betaARKct imparting cardioprotection. Post-I/R infarct size was greater in GRK2-overexpressing mice (45.0+/-2.8% versus 31.3+/-2.3% in controls) and significantly smaller in betaARKct mice (16.8+/-1.3%, P<0.05). Importantly, in vivo apoptosis was found to be consistent with these reciprocal effects on post-I/R myocardial injury when levels of GRK2 activity were altered. Moreover, these results were reflected by higher Akt activation and induction of NO production via betaARKct, and these antiapoptotic/survival effects could be recapitulated in vitro. Interestingly, selective antagonism of beta(2)ARs abolished betaARKct-mediated cardioprotection, suggesting that enhanced GRK2 activity on this GPCR is deleterious to cardiac myocyte survival. CONCLUSION: The novel effect of reducing acute ischemic myocardial injury via increased Akt activity and NO production adds significantly to the therapeutic potential of GRK2 inhibition with the betaARKct not only in chronic HF but also potentially in acute ischemic injury conditions. |
