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 g/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 colonystimulating factor also down-regulated tumor necrosis factor-␣ 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-apoptosis or regeneration.

The role of autophagy in the heart

“…Cardiomyocytes obtained from UM-7.1 hamsters, which is the model of human dilated cardiomyopathy, contain typical autophagic vacuoles, including degraded mitochondria, glycogen granules and myelin-like figures. 43 In diphtheria toxin receptor transgenic mice, degenerated cardiomyocytes showing characteristics of autophagy have also been observed. 44 However, the question remains as to whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for the failing cardiomyocytes.…”

Recycle or die: The role of autophagy in cardioprotection

“…Many studies have demonstrated that autophagy is upregulated in the heart in response to stress such as ischemia/reperfusion [4,[8][9][10][11][12]. Increased numbers of autophagosomes are a prominent feature in many cardiovascular diseases such as cardiac hypertrophy and heart failure [13][14][15][16][17][18]. However, the functional role of the enhanced autophagy in the diseased heart is unclear and studies have yielded conflicting results regarding the role of autophagy in the heart.…”

Myocyte Autophagy in Heart Disease: Friend or Foe?

“…17,18 Among these, activation of autophagic mechanisms has been detected in models of short-term nutrient deprivation, 15,19,20 chronic ischemia, 21 ischemia-reperfusion injury, 13,22 genetic cardiomyopathy, 23 and diphtheria toxin-induced injury. 24 Evidence of autophagic activity has been reported in patients with heart disease.…”