Cardiac GRK2 Ablation Induces a Novel Ca2+ Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction
Background—G-protein coupled receptor kinase 2 (GRK2) is a primary regulator of β-adrenergic signaling in the heart. GRK2 ablation ameliorates heart failure development but the cellular mechanisms have not been elucidated and are the aim of this study.
Methods and Results—Myocyte contractility, Ca2+ handling and excitation-contraction coupling were studied in isolated cardiomyocytes from wild-type (WT) and GRK2 knockout (GRK2KO) mice without (sham) or with myocardial infarction (MI). In cardiac myocytes isolated from unstressed WT and GRK2KO hearts, myocyte contractions and Ca2+ transients were similar but GRK2KO myocytes had lower sarcoplasmic reticulum (SR) Ca2+ content due to increased sodium-Ca2+ exchanger (NCX) activity and inhibited SR Ca2+ ATPase by local PKA mediated activation of PDE4 resulting in hypophosphorylated phospholamban. This Ca2+ handling phenotype is explained by a higher fractional SR Ca2+ release induced by increased L-type Ca2+ channel currents (ICa,L). After β-adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca2+ transients, which were not mediated through cardiac L-type Ca2+ channels (LTCCs), but through an increased SR Ca2+. Interestingly, post-MI GRK2KO mice showed better cardiac function than post-MI control mice, which is explained by an improved Ca2+ handling phenotype. The SR Ca2+ content was better maintained in post-MI GRK2KO myocytes than in post-MI control myocytes, due to better maintained ICa,L density and no increase in NCX in GRK2KO myocytes. An LTCC blocker, verapamil, reversed some beneficial effects of GRK2KO.
Conclusions—These data argue for novel differential regulation of ICa,L and SR load by GRK2. GRK2 ablation represents a novel beneficial Ca2+ handling phenotype resisting adverse remodeling after MI.
- experimental models heart failure
- heart failure
- Excitation Contraction Coupling
- G-Protein Coupled Receptor Kinase 2
- Received June 4, 2011.
- Accepted March 2, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited