Cardiac G-Protein-Coupled Receptor Kinase 2 Ablation Induces a Novel Ca2+ Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction
Cardiac G-Protein-Coupled Receptor Kinase 2 Ablation Induces a Novel Ca2+ Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction
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DOI：
10.1161/circulationaha.111.044255
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发表时间：
2012-05-01
期刊：
影响因子：
37.8
通讯作者：
Koch, Walter J.
中科院分区：
文献类型：
--
作者：
Raake, Philip W.;Zhang, Xiaoying;Koch, Walter J.
G蛋白偶联受体激酶2（GRK 2）是心脏β-肾上腺素能信号的主要调节因子。G-蛋白偶联受体激酶2消融阻碍心力衰竭的发展，但澄清的细胞机制尚未实现，这种澄清是本study.Methods和Results-Myocyte收缩性，Ca 2+处理和兴奋-收缩耦合研究了从野生型和GRK 2基因敲除（GRK 2KO）小鼠分离的心肌细胞没有（假）或心肌梗死（MI）的目的。在从未应激的野生型和GRK 2KO心脏中分离的心肌细胞中，肌细胞收缩和Ca 2+瞬变是相似的，但是GRK 2KO肌细胞具有较低的肌浆网（SR）Ca 2+含量，因为钠-Ca 2+交换活性增加，并且通过局部蛋白激酶A介导的磷酸二酯酶4的激活抑制SR Ca 2 + ATP酶，从而导致低磷酸化受磷蛋白。这种Ca 2+处理表型由增加的L-型Ca 2+通道电流诱导的较高分数SR Ca 2+释放解释。在β-肾上腺素能刺激后，GRK 2KO肌细胞显示收缩性和Ca 2+瞬变显著增加，这不是通过心脏L-型Ca 2+通道介导的，而是通过增加SR Ca 2+介导的。有趣的是，MI后GRK 2KO小鼠显示出比MI后对照小鼠更好的心脏功能，这可以通过改善的Ca 2+处理表型来解释。心肌梗死后GRK 2KO心肌细胞的SR Ca 2+含量比心肌梗死后对照心肌细胞维持得更好，因为GRK 2KO心肌细胞中L型Ca 2+通道电流密度维持得更好，钠-Ca 2+交换器没有增加。一个L-型钙通道阻滞剂，维拉帕米，逆转GRK2KO.Conclusions的一些有益的影响，这些数据认为新的差分调节L-型钙通道电流和SR负载GRK 2。G蛋白偶联受体激酶2消融代表了一种新的有益的钙处理表型，抵抗MI后的不良重塑。（循环。2012;125：2108-2118）。
Background-G-protein-coupled receptor kinase 2 (GRK2) is a primary regulator of beta-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 beta-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. (Circulation. 2012;125:2108-2118.)