G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure

Philip W. Raake, Leif E. Vinge, Erhe Gao, Matthieu Boucher, Giuseppe Rengo, Xiongwen Chen, Brent R. Degeorge, Scot Matkovich, Steven R. Houser, Patrick Most, Andrea D. Eckhart, Gerald W. Dorn, Walter J. Koch

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

Abstract

Myocardial G protein-coupled receptor kinase (GRK)2 is a critical regulator of cardiac β-adrenergic receptor (βAR) signaling and cardiac function. Its upregulation in heart failure may further depress cardiac function and contribute to mortality in this syndrome. Preventing GRK2 translocation to activated βAR with a GRK2-derived peptide that binds Gβγ (βARKct) has benefited some models of heart failure, but the precise mechanism is uncertain, because GRK2 is still present and βARKct has other potential effects. We generated mice in which cardiac myocyte GRK2 expression was normal during embryonic development but was ablated after birth (αMHC-Cre×GRK2 fl/fl) or only after administration of tamoxifen (αMHC-MerCreMer×GRK2 fl/fl) and examined the consequences of GRK2 ablation before and after surgical coronary artery ligation on cardiac adaptation after myocardial infarction. Absence of GRK2 before coronary artery ligation prevented maladaptive postinfarction remodeling and preserved βAR responsiveness. Strikingly, GRK2 ablation initiated 10 days after infarction increased survival, enhanced cardiac contractile performance, and halted ventricular remodeling. These results demonstrate a specific causal role for GRK2 in postinfarction cardiac remodeling and heart failure and support therapeutic approaches of targeting GRK2 or restoring βAR signaling by other means to improve outcomes in heart failure.

Original languageEnglish
Pages (from-to)413-422
Number of pages10
JournalCirculation research
Volume103
Issue number4
DOIs
StatePublished - Aug 15 2008

Keywords

  • Conditional gene targeting
  • GRK2
  • Heart failure
  • Myocardial infarction

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