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 andcell 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 autophagic findings, an increase in cardiomyocyte size, and a reduction in myocardial fibrosis. G-CSF inducedchanges in molecular signaling included activation of Akt and 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. By contrast, neither cardiomyocyte apoptosis nor regeneration of cardiomyocytes from bone marrowderived cells was significant. It thus appears that autophagic death is an importantcontributor to cardiomyocyte loss in the cardiomyopathic hamster and that G-CSF exerts a beneficial effect, mainly via an antiautophagic mechanism.Addendum to:Autophagic Cardiomyocyte Death in Cardiomyopathic Hamsters and Its Prevention by Granulocyte Colony-Stimulating FactorS. Miyata, G. Takemura, Y. Kawase, Y. Li, H. Okada, R. Maruyama, H. Ushikoshi, M. Esaki, H. Kanamori, L. Li, Y. Misao, A. Tezuka, T. Toyo-Oka, S. Minatoguchi, T. Fujiwara and H. FujiwaraAm J Pathol 2006; 168:386-97