Song Long-Sheng, Sobie Eric A, McCulle Stacey, Lederer W J, Balke C William, Cheng Heping
Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA.
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4305-10. doi: 10.1073/pnas.0509324103. Epub 2006 Mar 6.
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 Ca(2+) signaling. In heart failure, multiple cellular defects develop, including reduced contractility, altered Ca(2+) 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 Ca(2+) signaling that are related to restructuring of the spatial organization of the cells. Myocytes display both a reduced ability to trigger sarcoplasmic reticulum Ca(2+) 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 Z-line structures and leaving behind the sarcoplasmic reticulum Ca(2+) release channels, the ryanodine receptors (RyRs). These orphaned RyRs appear to be responsible for the dyssynchronous Ca(2+) sparks that have been linked to blunted contractility and, probably, Ca(2+)-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 Ca(2+) instability in heart failure.
心肌的特征是有规则排列的蛋白质和结构，这些形成了一个重复的功能单位，即肌节。这种规则结构使电活动与Ca(2+)信号能够紧密耦合。在心力衰竭中，会出现多种细胞缺陷，包括收缩力降低、Ca(2+)信号改变和心律失常；然而，这些缺陷的根本原因尚不清楚。在此，在出现心力衰竭的自发性高血压大鼠的心室肌细胞中，我们发现了与细胞空间组织重构相关的Ca(2+)信号的根本变化。肌细胞触发肌浆网Ca(2+)释放的能力降低，同时横管（TTs）的空间分散增加。来自衰竭心脏的细胞中重塑的TTs不再存在于正常心脏细胞中发现的规则组织结构中，而是在肌节内移动，远离Z线结构，留下肌浆网Ca(2+)释放通道，即兰尼碱受体（RyRs）。这些孤立的RyRs似乎是导致不同心力衰竭模型中与收缩力减弱以及可能与Ca(2+)依赖性心律失常相关的不同步Ca(2+)火花的原因。我们得出结论，TTs和孤立RyRs空间分散增加导致心力衰竭中局部控制丧失和Ca(2+)不稳定。
