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: 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 2nd, Walter J Koch
• Journal: Circulation research (Circ Res) Vol. 103 Issue 4 Pg. 413-22 (Aug 15 2008) ISSN: 1524-4571 [Electronic] United States
• PMID: 18635825 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Antagonists
• Receptors, Adrenergic, beta
• Tamoxifen
• GRK2 protein, mouse
• G-Protein-Coupled Receptor Kinase 2

Topics

• 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)