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(American Journal of Pathology. 2006;168:386-397.)
© 2006 American Society for Investigative Pathology

Autophagic Cardiomyocyte Death in Cardiomyopathic Hamsters and Its Prevention by Granulocyte Colony-Stimulating Factor

Shusaku Miyata^*, Genzou Takemura^*, Yukinori Kawase^*, Yiwen Li^*, Hideshi Okada^*, Rumi Maruyama^*, Hiroaki Ushikoshi^*, Masayasu Esaki^*, Hiromitsu Kanamori^*, Longhu Li^*, Yu Misao^*, Asaki Tezuka, Teruhiko Toyo-Oka, Shinya Minatoguchi^*, Takako Fujiwara and Hisayoshi Fujiwara^*

From the Second Department of Internal Medicine,^* Gifu University School of Medicine, Gifu; the Department of Organ Pathophysiology and Internal Medicine, University of Tokyo, Tokyo; and the Department of Food Science, Kyoto Women’s University, Kyoto, Japan

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 µg/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- 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-apo-ptosis or regeneration.

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