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Electrophysiological basis of metabolic-syndrome-induced cardiac dysfunction

机译:代谢综合征引起的心功能不全的电生理基础

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Myocardial contractility is controlled by intracellular Ca2+ cycling with the contribution of sarcoplasmic reticulum (SR). In this study, we aimed to investigate the role of altered SR function in defective regulation of intracellular Ca2+ levels in rats with metabolic syndrome (MetS) induced by a 16-week high-sucrose drinking-water diet. Electric-field stimulated transient intracellular Ca2+ changes in MetS cardiomyocytes exhibited significantly reduced amplitude (similar to 30%) and prolonged time courses (2-fold), as well as depressed SR Ca2+ loading (similar to 55%) with increased basal Ca2+ level. Consistent with these data, altered ryanodine receptor (RyR2) function and SERCA2a activity were found in MetS cardiomyocytes through Ca2+ spark measurements and caffeine application assay in a state in which sodium calcium exchanger was inhibited. Furthermore, tetracaine application assay results and hyperphosphorylated level of RyR2 also support the "leaky RyR2" hypothesis. Moreover, altered phosphorylation levels of phospholamban (PLN) support the depressed SERCA2a-activity thesis and these alterations in the phosphorylation of Ca2+-handling proteins are correlated with altered protein kinase and phosphatase activity in MetS cardiomyocytes. In conclusion, MetS-rat heart exhibits altered Ca2+ signaling largely due to altered SR function via changes in RyR2 and SERCA2a activity. These results point to RyR2 and SERCA2a as potential pharmacological targets for restoring intracellular Ca2+ homeostasis and, thereby, combatting dysfunction in MetS-rat heart.
机译:心肌收缩力是由细胞内Ca2 +循环控制的,并带有肌浆网(SR)。在这项研究中,我们旨在调查SR功能改变在16周高蔗糖饮用水饮食诱导的代谢综合征(MetS)大鼠中细胞内Ca2 +水平调控中的作用。 MetS心肌细胞中电场刺激的瞬时细胞内Ca2 +变化表现出幅度显着降低(约30%)和较长的时间进程(2倍),以及降低的SR Ca2 +负荷(约55%)和基础Ca2 +水平升高。与这些数据一致,通过钠钙交换剂被抑制的状态下的Ca2 +火花测量和咖啡因应用测定法,在MetS心肌细胞中发现了改变的ryanodine受体(RyR2)功能和SERCA2a活性。此外,丁卡因应用测定结果和RyR2的磷酸化水平也支持“渗漏的RyR2”假说。此外,磷酸lamban(PLN)磷酸化水平的改变支持了SERCA2a活性下降,这些Ca2 +处理蛋白磷酸化的改变与MetS心肌细胞中蛋白激酶和磷酸酶活性的改变有关。总之,由于RyR2和SERCA2a活性的改变导致SR功能改变,MetS大鼠心脏的Ca2 +信号传导也发生了改变。这些结果表明,RyR2和SERCA2a是恢复细胞内Ca2 +稳态并从而对抗MetS-rat心脏功能障碍的潜在药理靶标。

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