Level of G protein-coupled receptor kinase-2 determines myocardial ischemia/reperfusion injury via pro- and anti-apoptotic mechanisms

Circ Res. 2010 Oct 29;107(9):1140-9. doi: 10.1161/CIRCRESAHA.110.221010. Epub 2010 Sep 2.

Abstract

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 β-adrenergic receptor (βAR) signaling. Chronic HF studies have been performed with GRK2 knockout mice, as well as expression of the βARKct, 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 βARKct-expressing transgenic mice, a deleterious effect of GRK2 on in vivo myocardial I/R injury with βARKct 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 βARKct 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 βARKct, and these antiapoptotic/survival effects could be recapitulated in vitro. Interestingly, selective antagonism of β(2)ARs abolished βARKct-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 βARKct not only in chronic HF but also potentially in acute ischemic injury conditions.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / physiology*
  • Cells, Cultured
  • G-Protein-Coupled Receptor Kinase 2 / metabolism*
  • G-Protein-Coupled Receptor Kinase 2 / physiology
  • Mice
  • Mice, Transgenic
  • Myocardial Reperfusion Injury / enzymology*
  • Myocardial Reperfusion Injury / pathology*
  • Rats

Substances

  • Apoptosis Regulatory Proteins
  • G-Protein-Coupled Receptor Kinase 2