Calpain inhibition protects against virus-induced apoptotic myocardial injury.
Viral myocarditis is an important cause of human morbidity and mortality for which reliable and effective therapy is lacking. Using reovirus strain 8B infection of neonatal mice, a well-characterized experimental model of direct virus-induced myocarditis, we now demonstrate that myocardial injury results from apoptosis. Proteases play a critical role as effectors of apoptosis. The activity of the cysteine protease calpain increases in reovirus-infected myocardiocytes and can be inhibited by the dipeptide alpha-ketoamide calpain inhibitor Z-Leu-aminobutyric acid-CONH(CH(2))3-morpholine (CX295). Treatment of reovirus-infected neonatal mice with CX295 protects them against reovirus myocarditis as documented by (i) a dramatic reduction in histopathologic evidence of myocardial injury, (ii) complete inhibition of apoptotic myocardial cell death as identified by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling, (iii) a reduction in serum creatine phosphokinase, and (iv) improved weight gain. These findings are the first evidence for the importance of a calpain-associated pathway of apoptotic cell death in viral disease. Inhibition of apoptotic signaling pathways may be an effective strategy for the treatment of viral disease in general and viral myocarditis in particular.
DeBiasi
R L
RL
Departments of Pediatric Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Edelstein
C L
CL
Sherry
B
B
Tyler
K L
KL
D000818:Animals; D017209:Apoptosis; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D061945:Caspase Inhibitors; D003402:Creatine Kinase / Q000097:blood; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D004151:Dipeptides / Q000627:therapeutic use*; D051379:Mice; D009205:Myocarditis / Q000517:prevention & control*; D012088:Reoviridae Infections / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C090138:AK 295; D003402:Creatine Kinase; D002154:Calpain