title: Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor.
abstract: 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 microg/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-alpha 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.
authors.affiliation: Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Miyata
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Kawase
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ushikoshi
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Longhu
authors.initials: L
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Misao
authors.forename: Asaki
authors.initials: A
authors.lastname: Tezuka
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Toyo-Oka
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000517:prevention & control*; D002402:Cathepsin D / Q000378:metabolism; D006224:Cricetinae; D005355:Fibrosis / Q000378:metabolism / Q000517:prevention & control*; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D008297:Male; D008647:Mesocricetus; D008928:Mitochondria / Q000473:pathology; D009186:Myelin Sheath; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014617:Vacuoles; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D016179:Granulocyte Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; D002402:Cathepsin D; D020691:rab GTP-Binding Proteins