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Apoptosis in congestive heart failure induced by viral myocarditis in mice
T Yamada1, A Matsumori, W Z Wang
1Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan.
Insights
In viral myocarditis, apoptosis primarily affects infiltrating mononuclear cells, not cardiac myocytes. This study clarifies the role of programmed cell death in heart failure pathogenesis.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Chronic heart failure may involve progressive loss of cardiac myocytes.
- The role of apoptosis (programmed cell death) in heart failure pathogenesis in vivo is not well understood.
- Direct evidence of significant apoptosis in cardiac myocytes is limited.
Purpose of the Study:
- To investigate the role of apoptosis in viral myocarditis-induced heart failure.
- To determine if cardiac myocytes undergo significant apoptosis during viral myocarditis.
- To identify the cell types undergoing apoptosis in the affected heart.
Main Methods:
- Induction of encephalomyocarditis virus myocarditis in DBA/2 mice.
- Detection of apoptosis using DNA fragmentation assays and terminal transferase dUTP nick end labeling (TUNL).
- Immunohistochemical analysis for Fas antigen and Fas ligand.
Main Results:
- Apoptosis, indicated by DNA laddering and morphological changes, was evident 5-14 days post-infection.
- Fas antigen and Fas ligand were detected on infiltrating mononuclear cells.
- TUNL staining identified apoptotic infiltrating mononuclear cells, but not cardiac myocytes.
Conclusions:
- In viral myocarditis, infiltrating mononuclear cells are the primary source of apoptosis.
- Cardiac myocytes do not appear to undergo significant apoptosis in this model of heart failure.
- Apoptosis of immune cells, rather than cardiac myocytes, may be involved in the pathogenesis of viral myocarditis.
Abstract:
It has recently been speculated that progressive deterioration of left ventricular function in chronic heart failure is due to the ongoing loss of viable cardiac myocytes. However, as there is little direct evidence of significant apoptosis contributing to the pathogenesis in cardiac myocytes in vivo, the significance of apoptosis in heart failure remains to be clarified. We investigated the role of apoptosis in heart failure induced by encephalomyocarditis virus myocarditis. DBA/2 mice were inoculated with the virus (day 0), then killed, and their hearts were extracted 3 to 28 days later. Internucleosomal DNA fragmentation, chromatin binding dye staining, and in situ terminal transferase deoxyuridine triphosphate (dUTP) end-labeling were used to detect apoptosis. Internucleosomal DNA fragmentation (DNA ladder) was clearly demonstrated on days 5 to 14 in the virus-infected hearts when myocardial necrosis and infiltration of mononuclear cells were prominent in the hearts. Apoptotic cells demonstrated morphological changes typical of apoptosis (condensation of chromatin and nuclear fragmentation). Both Fas antigen and Fas ligand immunoreactivity were detected in the infiltrating mononuclear cells. The in situ terminal transferase dUTP end-labeling method demonstrated condensed nuclei of infiltrating mononuclear cells on day 7. However, nuclei of cardiac myocytes surrounded by the cellular infiltration were absent. The main source of apoptotic cells in the heart in mice with viral myocarditis appeared to be the infiltrating mononuclear cells.