Orphaned ryanodine receptors in the failing heart
Orphaned ryanodine receptors in the failing heart
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DOI：
10.1073/pnas.0509324103
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发表时间：
2006-03-14
影响因子：
11.1
通讯作者：
Cheng, HP
中科院分区：
文献类型：
--
作者：
Song, LS;Sobie, EA;Cheng, HP
心肌的特征是一系列规则的蛋白质和结构，这些蛋白质和结构形成了一个重复的功能单位，被称为肌节。这种规则的结构使得电活动和钙信号之间能够紧密耦合。在心力衰竭中，会出现多种细胞缺陷，包括收缩能力降低、钙信号改变和心律失常；然而，这些缺陷的潜在原因尚不清楚。在这里，在自发性高血压大鼠发展为心力衰竭的心室肌细胞中，我们发现了与细胞空间组织重组相关的钙信号的根本变化。心肌细胞触发肌浆网钙释放的能力降低，横管(TT)的空间弥散增加。衰竭心脏细胞中重塑的TT不再存在于正常心脏细胞中的规则组织结构中，而是在远离Vine结构的肌节内移动，留下肌浆网钙释放通道，即ryanodine受体(RyRs)。这些孤立的RyR似乎是导致钙离子火花不同步的原因，这些火花与钝化的收缩能力有关，可能还与不同心力衰竭模型中的钙依赖心律失常有关。我们的结论是，TT和孤立RYR空间离散度的增加导致了心力衰竭时局部控制力的丧失和钙离子的不稳定。
Heart muscle is characterized by a regular array of proteins and structures that form a repeating functional unit identified as the sarcomere. This regular structure enables tight coupling between electrical activity and Ca2+ signaling. In heart failure, multiple cellular defects develop, including reduced contractility, altered Ca2+ signaling, and arrhythmias; however, the underlying causes of these defects are not well understood. Here, in ventricular myocytes from spontaneously hypertensive rats that develop heart failure, we identify fundamental changes in Ca2+ signaling that are related to restructuring of the spatial organization of the cells. Myocytes display both a reduced ability to trigger sarcoplasmic reticulum Ca2+ release and increased spatial dispersion of the transverse tubules (TTs). Remodeled TTs in cells from failing hearts no longer exist in the regularly organized structures found in normal heart cells, instead moving within the sarcomere away from the Vine structures and leaving behind the sarcoplasmic reticulum Ca2+ release channels, the ryanodine receptors (RyRs). These orphaned RyRs appear to be responsible for the dyssynchronous Ca2+ sparks that have been linked to blunted contractility and, probably, Ca2+-dependent arrhythmias in diverse models of heart failure. We conclude that the increased spatial dispersion of the TTs and orphaned RyRs lead to the loss of local control and Ca2+ instability in heart failure.