Published online before print July 17, 2008, doi: 10.1161/CIRCRESAHA.107.168336
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Submitted on November 20, 2007
Revised on June 30, 2008
Accepted on July 3, 2008
G Protein–Coupled Receptor Kinase 2 Ablation in Cardiac Myocytes Before or After Myocardial Infarction Prevents Heart Failure
Philip W. Raake *;
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.
* To whom correspondence should be addressed. E-mail: Philip.Raake{at}jefferson.edu.
Myocardial G protein–coupled receptor kinase (GRK)2 is a critical regulator of cardiac 
-adrenergic receptor (AR) 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 AR with a GRK2-derived peptide that binds G
(ARKct) has benefited some models of heart failure, but the precise mechanism is uncertain, because GRK2 is still present and ARKct 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 AR 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 AR signaling by other means to improve outcomes in heart failure.
Key words: heart failure • myocardial infarction • conditional gene targeting • GRK2
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