Synchronous progression of calcium transient-dependent beating and sarcomere destruction in apoptotic adult cardiomyocytes
Synchronous progression of calcium transient-dependent beating and sarcomere destruction in apoptotic adult cardiomyocytes
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DOI：
10.1152/ajpheart.00669.2005
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发表时间：
2006-04-01
影响因子：
4.8
通讯作者：
Fujiwara, H
中科院分区：
文献类型：
--
作者：
Maruyama, R;Takemura, G;Fujiwara, H
在早期凋亡，成年心肌细胞显示不寻常的跳动，这表明可能参与异常的Ca 2+瞬变在启动这种细胞类型的凋亡过程。在跳动的同时，这些细胞显示出由细胞骨架解体引起的动态结构变化，这是相当迅速的。由于心肌细胞的特殊结构和广泛的细胞骨架，我们假设它在如此短的时间内降解将需要一个特别有效的机制。为了更好地理解这一机制，我们使用连续视频显微镜观察β-肾上腺素能刺激诱导的成年大鼠心肌细胞凋亡，同时记录细胞内Ca 2+浓度和细胞长度。在凋亡细胞中观察到Ca 2+瞬变和相应的节律性收缩和舒张（跳动）。Ca 2+瞬变和跳动的频率随时间逐渐增加，并伴随着细胞收缩。随着细胞收缩，Ca 2+瞬变的幅度下降，舒张期细胞内Ca 2+浓度增加，直到瞬变消失。L-型钙通道（硝苯地平）、兰尼碱受体（ryanodine receptor）、1，4，5-三磷酸肌醇受体（inositol 1，4，5-trisphosphate receptor）、肌浆内钙ATP酶（thapsigargin）和Na+/Ca 2+交换体（KB-R7943）的拮抗剂可显著抑制细胞凋亡的跳动和进展。跳动的心肌细胞的电子显微镜检查显示Z盘的进行性破裂。免疫组化分析和Western blot证实，Z盘组成蛋白（α-辅肌动蛋白，结蛋白，原肌球蛋白）的消失之前降解的其他细胞骨架蛋白。因此，在成年心肌细胞凋亡中，Ca 2+瞬变介导了由Z盘破裂引发的凋亡搏动和有效的肌节破坏。
During early apoptosis, adult cardiomyocytes show unusual beating, suggesting possible participation of abnormal Ca2+ transients in initiation of apoptotic processes in this cell type. Simultaneously with the beating, these cells show dynamic structural alteration resulting from cytoskeletal disintegration that is quite rapid. Because of the specialized structure and extensive cytoskeleton of cardiomyocytes, we hypothesized that its degradation in so short a time would require a particularly efficient mechanism. To better understand this mechanism, we used serial video microscopy to observe beta-adrenergic stimulation-induced apoptosis in isolated adult rat cardiomyocytes while simultaneously recording intracellular Ca2+ concentration and cell length. Trains of Ca2+ transients and corresponding rhythmic contractions and relaxations (beating) were observed in apoptotic cells. Frequencies of Ca2+ transients and beating gradually increased with time and were accompanied by cellular shrinkage. As the cells shrank, amplitudes of Ca2+ transients declined and diastolic intracellular Ca2+ concentration increased until the transients were lost. Beating and progression of apoptosis were significantly inhibited by antagonists against the L-type Ca2+ channel (nifedipine), ryanodine receptor (ryanodine), inositol 1,4,5-trisphosphate receptor (heparin), sarco(endo) plasmic Ca2+-ATPase (thapsigargin), and Na+/Ca2+ exchanger (KB-R7943). Electron-microscopic examination of beating cardiomyocytes revealed progressive breakdown of Z disks. Immunohistochemical analysis and Western blot confirmed that disappearance of Z disk constituent proteins (alpha-actinin, desmin, and tropomyosin) preceded degradation of other cytoskeletal proteins. It thus appears that, in adult cardiomyocyte apoptosis, Ca2+ transients mediate apoptotic beating and efficient sarcomere destruction initiated by Z disk breakdown.