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(Circulation Research. 2008;103:413.)
© 2008 American Heart Association, Inc.

Integrative Physiology

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, Jr, Scot Matkovich, Steven R. Houser, Patrick Most, Andrea D. Eckhart, Gerald W. Dorn, II, Walter J. Koch

From the George Zallie and Family Laboratory for Cardiovascular Gene Therapy (P.W.R., L.E.V., E.G., M.B., G.R., B.R.D., P.M., A.D.E., W.J.K.) and Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pa; Cardiovascular Research Center (X.C., S.R.H.), Department of Physiology, Temple University, Philadelphia, Pa; and Center for Pharmacogenomics (S.M., G.W.D.), Washington University, St Louis, Mo.

Correspondence to Philip W. Raake, MD, Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1025 Walnut St, Philadelphia, PA 19107. E-mail Philip.Raake{at}jefferson.edu

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 G_β (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 (MHC-CrexGRK2 fl/fl) or only after administration of tamoxifen (MHC-MerCreMerxGRK2 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.

Key Words: heart failure • myocardial infarction • conditional gene targeting • GRK2

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