Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor.
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.
Miyata
Shusaku
S
Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Takemura
Genzou
G
Kawase
Yukinori
Y
Li
Yiwen
Y
Okada
Hideshi
H
Maruyama
Rumi
R
Ushikoshi
Hiroaki
H
Esaki
Masayasu
M
Kanamori
Hiromitsu
H
Li
Longhu
L
Misao
Yu
Y
Tezuka
Asaki
A
Toyo-Oka
Teruhiko
T
Minatoguchi
Shinya
S
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
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
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