title: G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure.
abstract: Myocardial G protein-coupled receptor kinase (GRK)2 is a critical regulator of cardiac beta-adrenergic receptor (betaAR) 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 betaAR with a GRK2-derived peptide that binds G(beta)gamma (betaARKct) has benefited some models of heart failure, but the precise mechanism is uncertain, because GRK2 is still present and betaARKct has other potential effects. We generated mice in which cardiac myocyte GRK2 expression was normal during embryonic development but was ablated after birth (alphaMHC-Cre x GRK2 fl/fl) or only after administration of tamoxifen (alphaMHC-MerCreMer x 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 betaAR 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 betaAR signaling by other means to improve outcomes in heart failure.
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, 1025 Walnut St, Philadelphia, PA 19107, USA. Philip.Raake@jefferson.edu
authors.forename: Philip W
authors.initials: PW
authors.lastname: Raake
authors.forename: Leif E
authors.initials: LE
authors.lastname: Vinge
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Matthieu
authors.initials: M
authors.lastname: Boucher
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rengo
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Brent R
authors.initials: BR
authors.lastname: DeGeorge
authors.forename: Scot
authors.initials: S
authors.lastname: Matkovich
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Eckhart
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004965:Estrogen Antagonists / Q000494:pharmacology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D011943:Receptors, Adrenergic, beta; D013629:Tamoxifen; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2