Critical role for death-receptor mediated apoptotic signaling in viral myocarditis.
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.


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.
Department of Pediatrics, Children's National Medical Center and George Washington University School of Medicine, Washington, DC 20010, USA. rdebiasi@cnmc.org
Roberta L
RL
DeBiasi
Bridget A
BA
Robinson
J Smith
JS
Leser
R Dale
RD
Brown
Carlin S
CS
Long
Penny
P
Clarke
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D051379:Mice; D009205:Myocarditis / Q000473:pathology / Q000821:virology*; D032383:Myocytes, Cardiac / Q000473:pathology*; D051381:Rats; D053218:Receptors, Death Domain / Q000378:metabolism*; D012088:Reoviridae Infections / Q000378:metabolism; D015398:Signal Transduction
D053218:Receptors, Death Domain; D053148:Caspase 3; D053181:Caspase 8