Disruption of Smad5 gene induces mitochondria-dependent apoptosis in cardiomyocytes.
Disruption of Smad5 gene induces mitochondria-dependent apoptosis in cardiomyocytes.
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DOI：
10.1016/j.yexcr.2005.02.012
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发表时间：
2005-05
影响因子：
3.7
通讯作者：
Yanxun Sun;Jiang Zhou;Xudong Liao;Ya-xin Lü;C. Deng;Peitang Huang;Quan Chen;X. Yang
中科院分区：
文献类型：
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作者：
Yanxun Sun;Jiang Zhou;Xudong Liao;Ya-xin Lü;C. Deng;Peitang Huang;Quan Chen;X. Yang
SMAD 5是转化生长因子β（transforming growth factor β，TGF-β）家族的重要细胞内调节因子，是体内心血管系统正常发育所必需的。在目前的研究中，我们报道了Smad 5基因的缺失导致体内心肌细胞凋亡。为了进一步研究Smad 5基因在心肌细胞凋亡中的作用机制，采用胚胎干细胞（ES）分化系统。我们发现，从纯合Smad 5ex 6/ex 6突变ES细胞分化的肌管在体外分化的后期阶段经历了塌陷和变性，模仿体内观察。通过电子显微镜，观察到异常肿胀的线粒体在心肌细胞Smad 5缺陷的胚胎和ES分化的细胞。从Smad 5突变ES细胞分化的心肌细胞的线粒体膜电位（Δ Δ Km）也显著降低，细胞色素c从线粒体渗漏到胞质溶胶中。发现在分化的Smad 5突变体心肌细胞中p53和p21的表达升高，并且这伴随着caspase 3表达的上调。这些结果表明，Smad 5介导的TGF-β信号可能通过维持线粒体的完整性来保护心肌细胞免于凋亡，可能是通过抑制p53介导的途径。
Our previous studies have shown that SMAD5, an important intracellular mediator of transforming growth factor β (TGF-β) family, is required for normal development of the cardiovascular system in vivo. In the current study, we reported that the lack of the Smad5 gene resulted in apoptosis of cardiac myocytes in vivo. To further investigate the mechanism of the Smad5 gene in cardiomyocyte apoptosis, the embryonic stem (ES) cell differentiation system was employed. We found that the myotubes that differentiated from the homozygous Smad5ex6/ex6mutant ES cells underwent collapse and degeneration during the late stages of in vitro differentiation, mimicking the in vivo observation. By electron microscopy, abnormal swollen mitochondria were observed in cardiomyocytes both from Smad5-deficient embryos and from ES-differentiated cells. There was also a significant reduction in mitochondrial membrane potential (Δψm) and a leakage of cytochrome c from mitochondria into the cytosol of myocytes differentiated from Smad5 mutant ES cells. The expression of p53 and p21 was found to be elevated in the differentiated Smad5 mutant myocytes, and this was accompanied by an up-regulation in caspase 3 expression. These results suggest that the Smad5-mediated TGF-β signals may protect cardiomyocytes from apoptosis by maintaining the integrity of the mitochondria, probably through suppression of p53 mediated pathways.