Document Detail


G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure.
MedLine Citation:
PMID:  18635825     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-07-17
Journal Detail:
Title:  Circulation research     Volume:  103     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-15     Completed Date:  2008-09-05     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  413-22     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Disease Models, Animal
Estrogen Antagonists / pharmacology
G-Protein-Coupled Receptor Kinase 2 / genetics,  metabolism*
Gene Expression Regulation
Heart Failure / metabolism*,  pathology,  prevention & control
Ligation
Mice
Mice, Knockout
Mice, Transgenic
Myocardial Infarction / complications,  metabolism*,  pathology
Myocytes, Cardiac / drug effects,  metabolism*,  pathology
Receptors, Adrenergic, beta / metabolism
Tamoxifen / pharmacology
Grant Support
ID/Acronym/Agency:
P01 HL075443/HL/NHLBI NIH HHS; P01 HL075443/HL/NHLBI NIH HHS; P01 HL075443-050002/HL/NHLBI NIH HHS; R01 HL056205/HL/NHLBI NIH HHS; R01 HL056205-08/HL/NHLBI NIH HHS; R01 HL061690/HL/NHLBI NIH HHS; R01 HL061690-09/HL/NHLBI NIH HHS; R01 HL061690-10/HL/NHLBI NIH HHS; R01 HL061690-11/HL/NHLBI NIH HHS; R01 HL087871/HL/NHLBI NIH HHS; R01 HL088243/HL/NHLBI NIH HHS; R01 HL088243-01/HL/NHLBI NIH HHS; R01 HL088243-02/HL/NHLBI NIH HHS; R01 HL56205/HL/NHLBI NIH HHS; R01 HL61690/HL/NHLBI NIH HHS; R01 HL87871/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Estrogen Antagonists; 0/Receptors, Adrenergic, beta; 094ZI81Y45/Tamoxifen; EC 2.7.11.15/Adrbk1 protein, mouse; EC 2.7.11.15/G-Protein-Coupled Receptor Kinase 2
Comments/Corrections

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