Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction.

Authors

Philip W Raake, Department of Internal Medicine III, Cardiology, University of HeidelbergFollow
Xiaoying Zhang, Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine
Leif E Vinge, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow
Henriette Brinks, Center for Translational Medicine, Department of Medicine, Thomas Jefferson University
Erhe Gao, Center for Translational Medicine, Department of Pharmacology, Temple UniversityFollow
Naser Jaleel, Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine
Yingxin Li, Cardiovascular Research Center, Department of Physiology, Temple University School of MedicineFollow
Mingxin Tang, Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine
Patrick Most, Center for Translational Medicine, Department of Medicine, Thomas Jefferson UniversityFollow
Gerald W Dorn, Center for Pharmacogenomics, Washington UniversityFollow
Steven R Houser, Cardiovascular Research Center, Department of Physiology, Temple University School of MedicineFollow
Hugo A Katus, Department of Internal Medicine III, Cardiology, University of HeidelbergFollow
Xiongwen Chen, Cardiovascular Research Center, Department of Physiology, Temple University School of MedicineFollow
Walter J Koch, Center for Translational Medicine, Department of Pharmacology, Temple UniversityFollow

Document Type

Article

Publication Date

5-1-2012

Comments

This article has been peer reviewed and is published in Circulation.

Volume 125, Issue 17, 1 May 2012, Pages 2108-2118.

The published version is available at DOI: 10.1161/CIRCULATIONAHA.111.044255. © 2012 American Heart Association, Inc.

Abstract

BACKGROUND: G-protein-coupled receptor kinase 2 (GRK2) is a primary regulator of β-adrenergic signaling in the heart. G-protein-coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study.

METHODS AND RESULTS: Myocyte contractility, Ca(2+) handling and excitation-contraction coupling were studied in isolated cardiomyocytes from wild-type and GRK2 knockout (GRK2KO) mice without (sham) or with myocardial infarction (MI). In cardiac myocytes isolated from unstressed wild-type and GRK2KO hearts, myocyte contractions and Ca(2+) transients were similar, but GRK2KO myocytes had lower sarcoplasmic reticulum (SR) Ca(2+) content because of increased sodium-Ca(2+) exchanger activity and inhibited SR Ca(2+) ATPase by local protein kinase A-mediated activation of phosphodiesterase 4 resulting in hypophosphorylated phospholamban. This Ca(2+) handling phenotype is explained by a higher fractional SR Ca(2+) release induced by increased L-type Ca(2+) channel currents. After β-adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca(2+) transients, which were not mediated through cardiac L-type Ca(2+) channels but through an increased SR Ca(2+). Interestingly, post-MI GRK2KO mice showed better cardiac function than post-MI control mice, which is explained by an improved Ca(2+) handling phenotype. The SR Ca(2+) content was better maintained in post-MI GRK2KO myocytes than in post-MI control myocytes because of better-maintained L-type Ca(2+) channel current density and no increase in sodium-Ca(2+) exchanger in GRK2KO myocytes. An L-type Ca(2+) channel blocker, verapamil, reversed some beneficial effects of GRK2KO.

CONCLUSIONS: These data argue for novel differential regulation of L-type Ca(2+) channel currents and SR load by GRK2. G-protein-coupled receptor kinase 2 ablation represents a novel beneficial Ca(2+) handling phenotype resisting adverse remodeling after MI.

Recommended Citation

Raake, Philip W; Zhang, Xiaoying; Vinge, Leif E; Brinks, Henriette; Gao, Erhe; Jaleel, Naser; Li, Yingxin; Tang, Mingxin; Most, Patrick; Dorn, Gerald W; Houser, Steven R; Katus, Hugo A; Chen, Xiongwen; and Koch, Walter J, "Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction." (2012). Center for Translational Medicine Faculty Papers. Paper 17.
https://jdc.jefferson.edu/transmedfp/17

PubMed ID

22496128