Critical role for death-receptor mediated apoptotic signaling in viral myocarditis
Roberta L DeBiasi1, Bridget A Robinson, J Smith Leser
1Department of Pediatrics, Children's National Medical Center and George Washington University School of Medicine, Washington, DC 20010, USA. rdebiasi@cnmc.org
Background:
Apoptosis of cardiac myocytes plays a key role in the pathogenesis of many cardiac diseases, including viral myocarditis. The apoptotic signaling pathways that are activated during viral myocarditis and the role that these pathways play in disease pathogenesis have not been clearly delineated.
Methods And Results:
We investigated the role of apoptotic signaling pathways after virus infection of primary cardiac myocytes. The death receptor-associated initiator caspase, caspase 8, and the effector caspase, caspase 3, were significantly activated after infection of primary cardiac myocytes with myocarditic, but not non-myocarditic, reovirus strains. Furthermore, reovirus-induced cardiac myocyte apoptosis was significantly inhibited by soluble death receptors. In contrast, the mitochondrial membrane potential remained unaltered and caspase 9, the initiator caspase associated with mitochondrial apoptotic signaling, was only weakly activated in cardiac myocytes after infection with myocarditic reovirus strains. Inhibition of mitochondrial apoptotic signaling had no effect on reovirus-induced cardiac myocyte apoptosis. In accordance with our in vitro data, caspase 8, but not caspase 9, was significantly activated in the hearts of reovirus-infected mice.
Conclusions:
Death receptor, but not mitochondrial, apoptotic signaling plays a key role in apoptosis after infection of cardiac myocytes with myocarditic reovirus strains.
Insights
Viral myocarditis induces cardiac myocyte apoptosis via the death receptor pathway, activating caspase 8. Mitochondrial apoptotic signaling is not involved in this process.
Area of Science:
- Cardiology
- Virology
- Molecular Biology
Background:
- Apoptosis of cardiac myocytes is crucial in cardiac disease pathogenesis, including viral myocarditis.
- Specific apoptotic signaling pathways in viral myocarditis remain unclear.
Purpose of the Study:
- To investigate the role of apoptotic signaling pathways in cardiac myocyte apoptosis following viral infection.
- To determine whether death receptor or mitochondrial pathways are involved in reovirus-induced myocarditis.
Main Methods:
- Primary cardiac myocytes were infected with myocarditic and non-myocarditic reovirus strains.
- Apoptotic signaling was assessed by measuring caspase activation and mitochondrial membrane potential.
- Inhibition of specific apoptotic pathways was performed using soluble death receptors and caspase inhibitors.
- Cardiac tissue from reovirus-infected mice was analyzed for caspase activation.
Main Results:
- Myocarditic reovirus infection significantly activated caspase 8 and caspase 3 in cardiac myocytes.
- Reovirus-induced cardiac myocyte apoptosis was inhibited by soluble death receptors.
- Mitochondrial membrane potential was unaltered, and caspase 9 activation was minimal.
- Inhibition of mitochondrial pathways did not affect reovirus-induced apoptosis.
- Caspase 8, but not caspase 9, was activated in the hearts of infected mice.
Conclusions:
- The death receptor apoptotic signaling pathway is critical in cardiac myocyte apoptosis induced by myocarditic reovirus.
- Mitochondrial apoptotic signaling does not play a significant role in this viral myocarditis model.
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