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

• Verfasst von: Raake, Philip [VerfasserIn]
• Verfasst von: Most, Patrick [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Titel: Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction
• Verf.angabe: Philip W. Raake; Xiaoying Zhang; Leif E. Vinge; Henriette Brinks; Erhe Gao; Naser Jaleel; Yingxin Li; Mingxin Tang; Patrick Most; Gerald W. Dorn II; Steven R. Houser; Hugo A. Katus; Xiongwen Chen; Walter J. Koch
• E-Jahr: 2012
• Jahr: May 1, 2012
• Umfang: 11 S.
• Fussnoten: "2+" ist im Titel hochgestellt ; Gesehen am 20.11.2018
• Titel Quelle: Enthalten in: Circulation
• Ort Quelle: Philadelphia, Pa. : Lippincott, Williams & Wilkins, 1950
• Jahr Quelle: 2012
• Band/Heft Quelle: 125(2012), 17, Seite 2108-2118
• ISSN Quelle: 1524-4539
• DOI: doi:10.1161/CIRCULATIONAHA.111.044255
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1583874003

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, Ca2+ 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 Ca2+ transients were similar, but GRK2KO myocytes had lower sarcoplasmic reticulum (SR) Ca2+ content because of increased sodium-Ca2+ exchanger activity and inhibited SR Ca2+ ATPase by local protein kinase A-mediated activation of phosphodiesterase 4 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. After β-adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca2+ transients, which were not mediated through cardiac L-type Ca2+ channels 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 because of better-maintained L-type Ca2+ channel current density and no increase in sodium-Ca2+ exchanger in GRK2KO myocytes. An L-type Ca2+ channel blocker, verapamil, reversed some beneficial effects of GRK2KO.Conclusions—These data argue for novel differential regulation of L-type Ca2+ channel currents and SR load by GRK2. G-protein-coupled receptor kinase 2 ablation represents a novel beneficial Ca2+ handling phenotype resisting adverse remodeling after MI.