Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure
Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure
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DOI：
10.1016/s0008-6363(02)00230-4
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发表时间：
2002-04-01
影响因子：
10.8
通讯作者：
Kranias, EG
中科院分区：
文献类型：
--
作者：
Chu, GX;Carr, AN;Kranias, EG
目的：受损的肌细胞Ca 2+处理是衰竭心脏的常见特征，并且钙调神经磷酸酶（一种Ca 2+敏感性磷酸酶）活性的增加与心力衰竭表型有关。转基因小鼠心脏特异性表达的活性形式的钙调磷酸酶显示功能低下，肥大和心力衰竭。我们研究了钙调神经磷酸酶转基因小鼠心肌细胞Ca 2+处理特性的缺陷是否会导致心脏功能受损。研究方法：SR Ca 2+处理蛋白的水平，SR Ca 2+转运功能和心肌细胞力学，以及Ca 2+动力学进行了检查，在小鼠过表达的组成型活性形式的钙调磷酸酶。结果如下：转基因表达激活的钙调磷酸酶催化亚基导致SERCA 2蛋白显著增加（66%），受磷蛋白减少（35%），受磷蛋白磷酸化增强（接近80%）。SR Ca 2+转运蛋白的这些改变导致SERCA 2的V-max和Ca 2+亲和力增加。当pCa>6.0时，肌原纤维Mg-ATP酶活性也显著增加。增强的SR Ca 2+处理和Mg-ATP酶活性反映了肌细胞收缩参数（3倍）、Ca 2+瞬时振幅（1.5倍）和Ca 2+信号衰减速率（2倍）的显著升高。相反，在体内心脏功能评估超声心动图，表明严重抑郁的收缩钙调磷酸酶的心脏。细胞和多细胞制备物之间收缩特性的明显差异可能部分归因于组织重塑，包括间质纤维化和显著减少（45%）、去磷酸化（81%）和差距连接蛋白连接蛋白43的重新分布，这可能损害细胞间通讯。结论：尽管增强SR Ca 2+处理和收缩性的心肌细胞，病理性重塑和细胞间偶联的缺陷可能是钙调磷酸酶心脏收缩功能障碍的基础。(C)2002 Elsevier Science B. V.保留所有权利。
Objective: Impaired myocyte Ca2+ handling is a common characteristic of failing hearts and increases in calcineurin activity, a Ca2+-sensitive phosphatase, have been implicated in heart failure phenotype. Transgenic mice with cardiac-specific expression of an active form of calcineurin display depressed function, hypertrophy and heart failure. We examined whether defects in cardiomyocyte Ca2+ handling properties contribute to the impaired cardiac function in calcineurin transgenic mice. Methods: The levels of SR Ca2+ handling proteins, SR Ca2+ transport function and cardiomyocyte mechanics, as well as Ca2+ kinetics were examined in mice overexpressing a constitutively active form of calcineurin. Results: Transgenic expression of activated calcineurin catalytic subunit resulted in significant protein increases (66%) in SERCA2 and decreases (35%) in phospholamban, as well as enhanced (similar to80%) phospholamban phosphorylation. These alterations in the SR Ca2+-transport proteins resulted in increased V-max and Ca2+-affinity of SERCA2. The myofibrillar Mg-ATPase activity was also significantly increased at pCa>6.0. The enhanced SR Ca2+ handling and Mg-ATPase activity reflected significant elevation in myocyte contractile parameters (3-fold), Ca2+ transient amplitude (1.5-fold) and the rate of Ca2+ signal decay (2-fold). In contrast, in vivo cardiac function assessed by echocardiography, indicated severely depressed contractility in calcineurin hearts. The apparent disparity in contractile properties between the cellular and multicellular preparations may be partially due to tissue remodeling, including interstitial fibrosis and a marked reduction (45%), dephosphorylation (81%) and redistribution of the gap junctional protein connexin-43, which could compromise intercellular communication. Conclusion: Despite enhanced SR Ca2+ handling and contractility in myocytes, pathological remodeling and defects in intercellular coupling may underlie contractile dysfunction of the calcineurin hearts. (C) 2002 Elsevier Science B.V. All rights reserved.