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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Abnormal intrastore calcium signaling in chronic heart failure
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Abnormal intrastore calcium signaling in chronic heart failure

机译:慢性心力衰竭中店内钙信号异常

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Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intraluminal [Ca] in isolated cardiomyocytes and recordings from single-ryanodine receptor (RyR) channels reconstituted into lipid bilayers to investigate alterations in intracellular Ca handling in an experimental model of chronic HF. We found that diastolic free [Ca] inside the SIR was dramatically reduced because of a Ca leak across the SIR membrane, mediated by spontaneous local release events (Ca sparks), in HF myocytes. Additionally, the magnitudes of intrastore Ca depletion signals during global and focal Ca release events were blunted, and [Ca](SR) recovery was slowed after global but not focal Ca release in HF myocytes. At the single-RyR level, the sensitivity of RyRs to activation by luminal Ca was greatly enhanced, providing a molecular mechanism for the maintained potentiation of Ca sparks (and increased Ca leak) at reduced intra-SR [Ca] in HF. This work shows that the diminished SR Ca release characteristic of failing myocardium could be explained by increased sensitivity of RyRs to luminal Ca, leading to enhanced spark-mediated SR Ca leak and reduced intra-SR [Ca].
机译:从肌浆网(SR)释放的Ca减少是心脏衰竭的收缩力受损的重要原因。尽管付出了巨大努力,但心力衰竭(HF)中SR Ca异常释放的根本原因仍然未知。我们使用了在孤立的心肌细胞中胞浆和SR管腔内[Ca]的同时成像以及从重构成脂质双层的单ryanodine受体(RyR)通道记录的组合,以研究慢性HF实验模型中细胞内Ca处理的变化。我们发现,由于自发性局部释放事件(Ca火花)介导的HF心肌细胞中Ca跨SIR膜泄漏,SIR内的舒张自由[Ca]大大降低。另外,在整体和局灶性钙释放事件期间,店内钙耗竭信号的强度减弱,并且在HF肌细胞中整体而非局灶性Ca释放之后,[Ca](SR)恢复减慢。在单一RyR水平上,RyRs对腔内Ca活化的敏感性大大提高,这为在HF内SR内[Ca]降低时保持Ca火花增强(并增加Ca泄漏)提供了分子机制。这项工作表明,心肌衰竭时SR Ca释放特性减弱的原因可以是RyRs对腔内Ca的敏感性增加,从而导致火花介导的SR Ca泄漏增强和SR内[Ca]降低。

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