Ultrastructural remodelling of Ca(2+) signalling apparatus in failing heart cells.
Ultrastructural remodelling of Ca(2+) signalling apparatus in failing heart cells.
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DOI：
10.1093/cvr/cvs195
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发表时间：
2012-09
影响因子：
10.8
通讯作者：
Hao Wu;Ming Xu;Rong Li;Liang Guo;Ying-Si Lai;Shi-Ming Xu;Sufang Li;Quan-Long Lü;Lin-Lin Li-Lin;Haibo Zhang;You-yi Zhang;Chuan-Mao Zhang;Shi-Qiang Wang
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文献类型：
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作者：
Hao Wu;Ming Xu;Rong Li;Liang Guo;Ying-Si Lai;Shi-Ming Xu;Sufang Li;Quan-Long Lü;Lin-Lin Li-Lin;Haibo Zhang;You-yi Zhang;Chuan-Mao Zhang;Shi-Qiang Wang
目的心肌细胞收缩是由细胞膜/T-小管（TT）L型钙通道（LCC）和连接肌浆网（SR）ryanodine受体（RyR）之间的Ca（2+）诱导的Ca（2+）释放控制的。在心力衰竭期间，LCC-RyR信号传导变得有缺陷。本研究的目的是揭示潜在的缺陷LCC-RyR信号和收缩性的超微结构机制。方法与结果在主动脉缩窄术造成的大鼠心衰模型中，透射电镜图像的体视学分析显示，心衰心肌细胞中连接性SR和SR偶联性TT的体密度和表面积均减少。TT-SR连接点从Z线区域移位或缺失。此外，在衰竭的心脏细胞中，个体TT-SR连接的空间跨度显著减少。数值模拟和junctophilin-2敲低实验表明，结尺寸的减少（从而本构LCC和RyR数）导致Ca（2+）释放激活的分散延迟。结论：心衰时，心肌组织TT-SR连接的萎缩和缺失是导致心肌细胞钙释放不均匀和不均匀，收缩力下降的重要机制。因此，保持TT-SR连接的纳米级完整性代表了针对心力衰竭和相关心肌病的治疗策略。
AIMS The contraction of a heart cell is controlled by Ca(2+)-induced Ca(2+) release between L-type Ca(2+) channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (SR). During heart failure, LCC-RyR signalling becomes defective. The purpose of the present study was to reveal the ultrastructural mechanism underlying the defective LCC-RyR signalling and contractility. METHODS AND RESULTS In rat models of heart failure produced by transverse aortic constriction surgery, stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of junctional SRs and those of SR-coupled TTs were both decreased in failing heart cells. The TT-SR junctions were displaced or missing from the Z-line areas. Moreover, the spatial span of individual TT-SR junctions was markedly reduced in failing heart cells. Numerical simulation and junctophilin-2 knockdown experiments demonstrated that the decrease in junction size (and thereby the constitutive LCC and RyR numbers) led to a scattered delay of Ca(2+) release activation. CONCLUSIONS The shrinking and eventual absence of TT-SR junctions are important mechanisms underlying the desynchronized and inhomogeneous Ca(2+) release and the decreased contractile strength in heart failure. Maintaining the nanoscopic integrity of TT-SR junctions thus represents a therapeutic strategy against heart failure and related cardiomyopathies.