Changes in the organization of excitation-contraction coupling structures in failing human heart.
Changes in the organization of excitation-contraction coupling structures in failing human heart.
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DOI：
10.1371/journal.pone.0017901
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发表时间：
2011-03-09
期刊：
影响因子：
3.7
通讯作者：
Cannell MB
中科院分区：
文献类型：
--
作者：
Crossman DJ;Ruygrok PN;Soeller C;Cannell MB
心肌细胞t-管系统确保快速、均匀的细胞活化，几条实验证据表明，t-管系统和相关兴奋-收缩偶联蛋白的变化可能发生在心力衰竭中。使用高分辨率荧光成像，在正常和衰竭心脏（特发性（非缺血性）扩张型心肌病）的固定心室组织样本中检查了t-小管、L-型钙通道（DHPR）、兰尼碱受体（RyR）和收缩机制。麦胚凝集素（WGA），钠钙交换，DHPR和小窝蛋白-3标签显示，从主要的横向方向倾斜和轴向方向在失败的心肌细胞的转变。失败时，外周t-小管扩张，蛋白质糖基化程度明显改变。肌丝（鬼笔环肽标记）所占面积分数没有变化，但单位面积RyR簇的数量略有减少。在正常心脏中，DHPR与RyR的一般关系没有改变，RyR标记与DHPR标记的重叠率为51±3%。在纵向（但不是横向）切片中，在衰竭心脏中通过Pearson相关系数测量的DHPR和RyR之间的共定位程度降低了约30%。结果表明，在衰竭的人类心脏中，t-管网络和相关的兴奋-收缩偶联蛋白发生了广泛的重塑。这些变化可能导致心力衰竭时钙处理异常。t系统的一般组织和在失效样本中观察到的变化与某些动物模型存在细微差异，尽管变化的一般方向通常相似。
The cardiac myocyte t-tubular system ensures rapid, uniform cell activation and several experimental lines of evidence suggest changes in the t-tubular system and associated excitation-contraction coupling proteins may occur in heart failure. The organization of t-tubules, L-type calcium channels (DHPRs), ryanodine receptors (RyRs) and contractile machinery were examined in fixed ventricular tissue samples from both normal and failing hearts (idiopathic (non-ischemic) dilated cardiomyopathy) using high resolution fluorescent imaging. Wheat germ agglutinin (WGA), Na-Ca exchanger, DHPR and caveolin-3 labels revealed a shift from a predominantly transverse orientation to oblique and axial directions in failing myocytes. In failure, dilation of peripheral t-tubules occurred and a change in the extent of protein glycosylation was evident. There was no change in the fractional area occupied by myofilaments (labeled with phalloidin) but there was a small reduction in the number of RyR clusters per unit area. The general relationship between DHPRs and RyR was not changed and RyR labeling overlapped with 51±3% of DHPR labeling in normal hearts. In longitudinal (but not transverse) sections there was an ∼30% reduction in the degree of colocalization between DHPRs and RyRs as measured by Pearson's correlation coefficient in failing hearts. The results show that extensive remodelling of the t-tubular network and associated excitation-contraction coupling proteins occurs in failing human heart. These changes may contribute to abnormal calcium handling in heart failure. The general organization of the t-system and changes observed in failure samples have subtle differences to some animal models although the general direction of changes are generally similar.
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