Stretch-Dependent Calcium Signaling in Heart

摘要 PI显示，心脏中的Ca 2+火花发生在生理条件下， 心脏收缩它们不仅是正常的[Ca 2 +]i瞬变的基础，而且被发现在 介导细胞对压力和疾病的反应，导致心脏收缩和舒张功能障碍， 从钙超载到肌营养不良的心肌病。最近， PI显示，生理拉伸，如心肌细胞在舒张充盈期间所经历的拉伸，显著地 改变正常心室肌细胞中Ca 2+火花的短暂发生。这种行为取决于 微管影响肌浆网（SR）的释放机制。尽管重要的是 一年前的这一新发现，我们直到现在才开发出研究如何 动态长度变化可以影响在不同条件下的Ca 2+火花的触发。使用这些新 工具，我们观察到（在初步调查），拉伸依赖的变化，钙火花甚至更大 比以前观察到的，似乎是由于兰尼碱的敏感性的瞬时增加引起的。 受体（RyR 2）。额外的初步工作表明，令人惊讶的是，这种瞬时增加的Ca 2+火花， 在对照小鼠的心脏细胞中，以非常低的速率激活致心律失常的Ca 2+波，但在 mdx小鼠、杜氏肌营养不良小鼠模型或 PI和他的同事们开发的工具将使 一个创新的国家的最先进的调查如何心脏Ca 2+信号调制的生理 伸展。拟议的工作旨在研究拉伸依赖的钙火花和钙波1。控制 心室肌细胞; 2. RyR 2特性发生改变的心室肌细胞; 3.心室 当微管被调制时，肌细胞; 4.来自肌营养不良蛋白缺失（mdx）小鼠的心室肌细胞。的 计划中的研究应该首次揭示拉伸在正常和病理性Ca 2+中的重要性。 心室肌细胞的信号传导。因此，这项工作不仅将提供基本的新的 关于正常细胞行为的信息，以及关于肿瘤发生机制的信息。此外，它将奠定 为各种心脏病包括杜氏肌营养不良症的新疗法奠定了基础。

Abstract Ca2+ sparks in heart have been shown by the PI to occur under physiological conditions during diastole and systole. They not only underlie the normal [Ca2+]i transient but have been found to be critically important in mediating the cellular response to stress and disease, contributing to contractile and arrhythmic dysfunction in conditions ranging from calcium overload to the cardiomyopathy of muscular dystrophy. Recently, work by the PI shows that physiologic stretch, such as that experienced by a myocyte during diastolic filling, dramatically alters Ca2+ spark occurrence transiently in normal cardiac ventricular myocytes. This behavior depends on microtubules affecting the release mechanisms of the sarcoplasmic reticulum (SR). Despite the importance of this new discovery one year ago, we have only now developed the additional tools needed to investigate how dynamic length changes can affect the triggering of Ca2+ sparks under diverse conditions. Using these new tools, we observe (in preliminary investigations) that stretch-dependent changes in Ca2+ sparks are even larger than previously observed and appear to arise from a transient increase in the the sensitivity of ryanodine receptors (RyR2s). Additional preliminary work shows that, surprisingly, this transient increase in Ca2+ sparks underlies the activation of arrhythmogenic Ca2+ waves at a very low rate in heart cells from control mice, but at a much higher rate in myocytes from mdx mice, the murine model of Duchenne muscular dystrophy, or from control mice with excessive calcium in the SR. The tools developed by the PI and his colleagues will enable an innovative state-of-the-art investigation into how cardiac Ca2+ signaling is modulated by physiological stretch. The proposed work seeks to investigate stretch-dependent Ca2+ sparks and Ca2+ waves in 1. control ventricular myocytes; 2. ventricular myocytes in which RyR2 properties have been altered; 3. ventricular myocytes when microtubules are modulated; 4. ventricular myocytes from dystrophin null (mdx) mice. The planned research should reveal for the first time the importance of stretch in normal and pathological Ca2+ signaling of cardiac ventricular myocytes. The work will therefore provide not only fundamental new information on normal cellular behavior but also on mechanisms of arrhythmogenesis. Furthermore it will lay the foundation for novel therapies for diverse heart diseases including Duchenne muscular dystrophy.