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Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating
Shusaku Miyata1, Genzou Takemura, Yukinori Kawase
1Second Department of Internal Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Insights
Autophagic cell death drives heart failure in a hamster model. Granulocyte colony-stimulating factor treatment improved survival by reducing this autophagic process, not by promoting regeneration.
Area of Science:
- Cardiology
- Cell Biology
- Pharmacology
Background:
- Dilated cardiomyopathy leads to progressive heart failure and mortality.
- The UM-X7.1 hamster model exhibits significant mortality by 30 weeks.
- Cardiomyocyte loss is a key feature of heart failure progression.
Purpose of the Study:
- To investigate the mechanism of cardiomyocyte loss in the UM-X7.1 hamster model.
- To evaluate the therapeutic effect of granulocyte colony-stimulating factor (G-CSF) on dilated cardiomyopathy.
- To elucidate the mechanism underlying G-CSF's beneficial effects.
Main Methods:
- Ultrastructural analysis of cardiomyocytes.
- Immunoassays for protein expression (ubiquitin, cathepsin D, Rab7).
- Assessment of G-CSF treatment effects on survival, cardiac function, histology, and molecular markers.
Main Results:
- Cardiomyocytes showed autophagic vacuoles and cathepsin D overexpression, linked to cell death, with minimal apoptosis.
- G-CSF treatment significantly improved survival (100% vs. 53%) and cardiac function.
- G-CSF reduced autophagic markers, myocardial fibrosis, and inflammation (TNF-α), while activating Akt and STAT3 signaling.
Conclusions:
- Autophagic cell death is a critical mechanism of cardiomyocyte loss in this dilated cardiomyopathy model.
- G-CSF exerts beneficial effects primarily through an anti-autophagic mechanism.
- G-CSF's action is not mediated by anti-apoptosis or direct cardiomyocyte regeneration.
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.
