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J. Virol. 75 (1): 351-361

Copyright © 2001 by the American Society for Microbiology. All rights reserved.

Journal of Virology, January 2001, p. 351-361, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.351-361.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Calpain Inhibition Protects against Virus-Induced Apoptotic Myocardial Injury

Roberta L. DeBiasi,1,2,3 Charles L. Edelstein,4 Barbara Sherry,5 and Kenneth L. Tyler2,3,4,6,*

Departments of Pediatric Infectious Diseases,1 Neurology,2 Medicine,4 and Microbiology and Immunology,6 University of Colorado Health Sciences Center, and Denver Veterans Affairs Medical Center,3 Denver, Colorado 80262, and Department of Microbiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 276065

Received 23 May 2000/Accepted 14 September 2000

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(CH2)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.

* Corresponding author. Mailing address: Department of Neurology (B-182), University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262. Phone: (303) 393-2874. Fax: (303) 393-4686. E-mail: Ken.Tyler{at}UCHSC.edu.

Journal of Virology, January 2001, p. 351-361, Vol. 75, No. 1
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.1.351-361.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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