title: Disruption of Smad5 gene induces mitochondria-dependent apoptosis in cardiomyocytes.
abstract: Our previous studies have shown that SMAD5, an important intracellular mediator of transforming growth factor beta (TGF-beta) 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/ex6 mutant 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 (Deltapsi m) 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-beta signals may protect cardiomyocytes from apoptosis by maintaining the integrity of the mitochondria, probably through suppression of p53 mediated pathways.
authors.affiliation: Genetic Laboratory of Development and Diseases, Institute of Biotechnology, 20 Dongdajie, Fengtai, Beijing 100071, PR China. yangx@nic.bmi.ac.cn
authors.forename: Yanxun
authors.initials: Y
authors.lastname: Sun
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhou
authors.forename: Xudong
authors.initials: X
authors.lastname: Liao
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Lü
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Peitang
authors.initials: P
authors.lastname: Huang
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D051902:Smad5 Protein; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases