Autophagic degeneration and death of cardiomyocytes in heart failure.
Numerous cardiomyocytes were found to show autophagic vacuolar degeneration in the UM-X7.1 hamster model of human dilated cardiomyopathy, and autophagy-related proteins--i.e., ubiquitin, cathepsin D and Rab7--were upregulated in those hearts. Importantly, Evans blue-positive cardiomyocytes with leaky plasma membranes were also positive for cathepsin D, suggesting a link between autophagic degeneration and cell death. Treatment with granulocyte colony-stimulating factor (G-CSF) significantly improved survival, cardiac function and remodeling in these animals, and such beneficial effects were accompanied by a reduction in autophagy, an increase in cardiomyocyte size, and a reduction in myocardial fibrosis. G-CSF-induced changes in molecular signaling included activation of Akt and Stat3 (signal transducer and activator of transcription-3), a reduction in the level of myocardial tumor necrosis factor-alpha, and an increase in those of matrix metalloproteinases. In contrast, neither cardiomyocyte apoptosis nor regeneration of cardiomyocytes from bone marrow-derived cells was significant. It thus appears that autophagic death and autophagy-dependent degeneration are important contributors to loss of cardiomyocyte function in the cardiomyopathic hamster and that G-CSF exerts a beneficial effect, mainly via an anti-autophagic mechanism.
Takemura
Genzou
G
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Miyata
Shusaku
S
Kawase
Yukinori
Y
Okada
Hideshi
H
Maruyama
Rumi
R
Fujiwara
Hisayoshi
H
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000473:pathology; D006224:Cricetinae; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000473:pathology*; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000473:pathology*
D016179:Granulocyte Colony-Stimulating Factor