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Apoptosis and oncosis in the early progression of left ventricular dysfunction in the cardiomyopathic hamster
Tsutomu Ryoke1, Yusu Gu, Yasuhiro Ikeda
1Shimonoseki Kosei Hospital, Department of Cardiology, Yamaguchi, Japan.
Insights
Myocyte oncosis, not apoptosis, is the primary cause of heart muscle cell death and early heart dysfunction in cardiomyopathic hamsters. This finding is crucial for understanding heart failure mechanisms.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Cellular Pathology
Background:
- Cardiomyopathic (CM) hamsters exhibit a genetic defect affecting the glycoprotein-sarcoglycan component of the dystrophin-glycoprotein complex.
- Dystrophin deficiency in mice is linked to apoptosis in skeletal muscle, prompting investigation into myocardial apoptosis versus oncosis in CM hamsters.
Purpose of the Study:
- To assess the roles of myocardial apoptosis and oncosis in causing myocardial necrosis during the onset of left ventricular (LV) dysfunction in CM hamsters.
- To evaluate the progression of LV dysfunction and cellular changes in CM hamsters compared to normal controls.
Main Methods:
- Echocardiography was used to assess LV size and function in normal and CM hamsters at 1, 2, 3, and 5 months of age.
- In situ end-labeling (TUNEL) and immunolabeling identified apoptotic nuclei; DNA fragmentation and nuclear morphology were also analyzed.
- Myocyte oncotic necrosis was evaluated using Evans blue dye (EBD) staining, wheat germ agglutinin, hematoxylin/eosin staining, and electron microscopy.
Main Results:
- A significant decrease in LV fractional shortening (45%) occurred between 1 and 2 months of age in CM hamsters.
- Apoptotic myocyte nuclei were minimal (average 0.041%) and not significantly increased at 2 months; DNA laddering was absent.
- Myocyte oncosis, characterized by sarcolemmal rupture and inflammatory infiltration, was evident, with 9.82% of myocardial area affected at 2 months, correlating with a 32% decrease in myocyte nuclei density.
Conclusions:
- Myocyte oncosis is the predominant mechanism driving the reduction in myocyte nuclei and early cardiac dysfunction in CM hamsters.
- Myocyte apoptosis plays a minor role in the observed myocardial necrosis and functional decline during the early stages of cardiomyopathy in this model.
- These findings highlight oncosis as a key pathological process in the progression of heart failure in CM hamsters.
Abstract:
The genetic defect in the cardiomyopathic (CM) hamster is a mutation in the glycoprotein-sarcoglycan (a component of the dystrophin-glycoprotein complex). Apoptosis has been identified in skeletal muscle of dystrophin-deficient mice, and therefore the role of myocardial apoptosis in relation to oncosis in causing myocardial necrosis was assessed at the onset of left ventricular (LV) dysfunction in CM hamsters. LV size and function were evaluated in normal and CM hamsters (CHF147 line) by echocardiography at 1, 2, 3, and 5 months (mo) of age. The decrease of LV fractional shortening was found to be most marked (45%) between 1 and 2 mo of age. Apop totic nuclei were identified at each time point using in situ end-labeling of DNA strand breaks (TUNEL), together with immunolabeling of myocytes; DNA fragmentation (laddering) and nuclear morphology were also assessed. Myocyte oncotic necrosis was assessed at 2 mo by Evans blue dye (EBD), wheat germ agglutinin, hematoxylin/eosin staining, and electron microscopy. Apoptotic nuclei were not detected in age-matched normal hamsters. In the CM hamsters apoptotic myocyte nuclei comprised an average of 0.041% of myocyte nuclei between 1 and 5 mo, an increase at 2 mo (to 0.076%) was not significant, and DNA laddering was not detected. The number of myocyte nuclei per unit area decreased by 32% between 1 and 2 mo, and in 2 mo old CM hamsters myocardial staining with EBD was positive in 9.82% of the myocardial cross sectional areas examined, most of which was consistent with sarcolemmal rupture and oncosis with inflammatory cell infiltration. It is concluded that myocyte oncosis provides the major mechanism for the decreased number of myocyte nuclei and the early decrease of cardiac function between 1 and 2 mo of age in the CM hamster, with only a small contribution of myocyte apoptosis.
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