Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor
Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor
复制标题
DOI：
10.2353/ajpath.2006.050137
复制
发表时间：
2006-02-01
影响因子：
6
通讯作者：
Fujiwara, H
中科院分区：
文献类型：
--
作者：
Miyata, S;Takemura, G;Fujiwara, H
在人扩张型心肌病的UM-X7.1仓鼠模型中，心力衰竭进行性发展并在30周龄时导致50%的死亡率。超微结构观察发现，该模型心肌细胞内有典型的自噬空泡，包括降解的线粒体、糖原颗粒和髓鞘样结构。此外，免疫分析表明，泛素、组织蛋白酶D和Rab 7均过表达。重要的是，大多数质膜渗漏的心肌细胞对组织蛋白酶D呈阳性，表明自噬变性和细胞死亡之间存在直接联系。心肌细胞凋亡不明显。粒细胞集落刺激因子（10 μ g/kg/天），从15 - 30周龄每周注射5天，提高了30周龄仓鼠的存活率（100%对未治疗仓鼠的53%，P < 0.0001）;还观察到心室功能和重塑，心肌细胞大小增加，心肌纤维化减少，随后自噬现象显著减少。粒细胞集落刺激因子还下调肿瘤坏死因子-a，并增加Akt信号转导和转录激活因子-3和基质金属蛋白酶的活性。然而，没有明确的证据表明骨髓细胞转分化为心肌细胞。总之，自噬死亡是心肌病仓鼠心肌细胞损失的重要因素，粒细胞集落刺激因子的有益作用主要是通过抗自噬机制，而不是抗凋亡或再生。
In UM-X7.1 hamster model of human dilated cardiomyopathy, heart failure progressively develops and causes 50% mortality by 30 weeks of age. Through ultrastructural analysis, we found that many cardiomyocytes of this model contain typical autophagic vacuoles including degraded mitochondria, glycogen granules, and myelin-like figures. In addition, ubiquitin, cathepsin D, and Rab7 were overexpressed as determined by immunoassays. Importantly, most cardiomyocytes with leaky plasma membranes were positive for cathepsin D, suggesting a direct link between autophagic degeneration and cell death. Meanwhile, cardiomyocyte apoptosis appeared insignificant. Granulocyte colony-stimulating factor (10 mu g/kg/day), injected 5 days/week from 15 to 30 weeks of age, improved survival among 30-week-old hamsters (100% versus 53% in the untreated hamsters, P < 0.0001); ventricular function and remodeling, increased cardiomyocyte size, and reduced myocardial fibrosis followed by a dramatic reduction in the autophagic findings were also seen. Granulocyte colony-stimulating factor also down-regulated tumor necrosis factor-a and increased activities of Akt signal transducer and activator of transcription-3, and matrix metalloproteinases. However, there was no clear evidence of transdifferentiation from bone marrow cells into cardiomyocytes. In conclusion, autophagic death is important for cardiomyocyte loss in the cardiomyopathic hamster, and the beneficial effect of granulocyte colony-stimulating factor acts mainly via an anti-autophagic mechanism rather than anti-apoptosis or regeneration.