Cardiac G-Protein–Coupled Receptor Kinase 2 Ablation Induces a Novel Ca 2+ Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction

Ovid Technologies (Wolters Kluwer Health) - Tập 125 Số 17 - Trang 2108-2118 - 2012
Philip Raake1,2,3,4, Xiaoying Zhang1,2,3,5, Leif Erik Vinge1,2,3,6, Henriette Brinks1,2,3,7, Erhe Gao1,2,8,3, Naser Jaleel1,2,3,9, Yingxin Li1,2,3,10, Ming‐Xin Tang1,2,3,11, Patrick Most1,2,3,12, Gerald W. Dorn1,2,3,13, Steven R. Houser1,2,3,14, Hugo A. Katus1,2,3,15, Xiongwen Chen1,2,3,16, Walter J. Koch1,2,3,17
1Center for Pharmacogenomics, Washington University, St. Louis, MO (G.W.D.).
2Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA
3From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St...
4Philip W. Raake From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
5Xiaoying Zhang From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
6Leif E. Vinge From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
7Henriette Brinks From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
8Erhe Gao From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
9Naser Jaleel From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
10Yingxin Li From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
11Mingxin Tang From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
12Patrick Most From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
13Gerald W. DornII From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
14Steven R. Houser From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
15Hugo A. Katus From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
16Xiongwen Chen From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)
17Walter J. Koch From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.)

Tóm tắt

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.

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Ovid Technologies (Wolters Kluwer Health)

Tập 125 Số 17

2108-2118

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