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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure
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Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure

机译：增强钙结合蛋白与雷诺丁受体的结合可改善心力衰竭患者的心脏和骨骼肌功能

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摘要

Abnormalities in intracellular calcium release and reuptake are responsible for decreased contractility in heart failure (HF). We have previously shown that cardiac ryanodine receptors (RyRs) are protein kinase A-hyperphosphorylated and depleted of the regulatory subunit calstabin-2 in HE Moreover, similar alterations in skeletal muscle RyR have been linked to increased fatigability in HE To determine whether restoration of calstabin binding to RyR may ameliorate cardiac and skeletal muscle dysfunction in HF, we treated WT and calstabin-2(-/-) mice subjected to myocardial infarction (Ml) with JTV519. JTV519, a 1,4-benzothiazepine, is a member of a class of drugs known as calcium channel stabilizers, previously shown to increase calstabin binding to RyR. Echocardiography at 21 days after Ml demonstrated a significant increase in ejection fraction in WT mice treated with JTV519 (45.8 +/- 5.1%) compared with placebo (31.1 +/- 3.1%; P < 0.05). Coimmunoprecipitation experiments revealed increased amounts of calstabin-2 bound to the RyR2 channel in JTV519-treated WT mice. However, JTV519 did not show any of these beneficial effects in calstabin2(-/-) mice with MI. Additionally, JTV519 improved skeletal muscle fatigue in WT and calstabin-2(-/-) mice with HF by increasing the binding of calstabin-1 to RyR1. The observation that treatment with JTV519 improved cardiac function in WT but not calstabin2(-/-) mice indicates that calstabin-2 binding to RyR2 is required for the beneficial effects in failing hearts. We conclude that JTV519 may provide a specific way to treat the cardiac and skeletal muscle myopathy in HF by increasing calstabin binding to RyR.
机译：细胞内钙的释放和再摄取异常是导致心力衰竭（HF）收缩力下降的原因。先前我们已经证明心脏瑞丹碱受体（RyRs）是蛋白激酶A的高磷酸化和HE中调节亚基calstabin-2的耗尽。此外，骨骼肌RyR的类似变化也与HE的易燃性有关。与RyR的结合可能会改善HF中的心脏和骨骼肌功能障碍，我们用JTV519治疗了遭受心肌梗死（M1）的WT和calstabin-2（-/-）小鼠。 JTV519是一种1,4-苯并硫氮杂pine，是一类药物的成员，称为钙通道稳定剂，以前被证明可增加钙稳定蛋白与RyR的结合。与安慰剂（31.1 +/- 3.1％； P <0.05）相比，M1后21天的超声心动图显示，经JTV519治疗的WT小鼠的射血分数显着增加（45.8 +/- 5.1％）。免疫共沉淀实验显示，在经JTV519处理的WT小鼠中，与RyR2通道结合的calstabin-2数量增加。但是，JTV519在具有MI的calstabin2（-/-）小鼠中未显示任何这些有益作用。此外，JTV519通过增加calstabin-1与RyR1的结合，改善了HF的WT和calstabin-2（-/-）小鼠的骨骼肌疲劳。用JTV519治疗可改善WT的心脏功能但不能改善calstabin2（-/-）小鼠的心脏功能，这一观察结果表明，calstabin-2与RyR2的结合对于心脏衰竭患者的有益作用是必需的。我们得出的结论是，JTV519可能通过增加钙结合蛋白与RyR的结合来提供治疗HF中的心脏和骨骼肌肌病的特定方法。

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