Cardiac G-protein-coupled receptor kinase 2 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. 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 th...
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| Hauptverfasser: | , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
May 1, 2012
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| In: |
Circulation
Year: 2012, Jahrgang: 125, Heft: 17, Pages: 2108-2118 |
| ISSN: | 1524-4539 |
| DOI: | 10.1161/CIRCULATIONAHA.111.044255 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1161/CIRCULATIONAHA.111.044255 Verlag, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.044255 
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| Verfasserangaben: | 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 |
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| 245 | 1 | 0 | |a Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction |c 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 |
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| 520 | |a 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. | ||
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