This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by DeBiasi, R. L.
Right arrow Articles by Tyler, K. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by DeBiasi, R. L.
Right arrow Articles by Tyler, K. L.

 Previous Article  |  Next Article 

Journal of Virology, October 2004, p. 11040-11050, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.11040-11050.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Caspase Inhibition Protects against Reovirus-Induced Myocardial Injury In Vitro and In Vivo

Roberta L. DeBiasi,1,2,3* Bridget A. Robinson,1 Barbara Sherry,4 Ron Bouchard,5 R. Dale Brown,6 Mona Rizeq,3,7 Carlin Long,6 and Kenneth L. Tyler2,3,6,8,9

Departments of Pediatrics,1 Neurology,2 Medicine,6 Pathology,7 Microbiology,8 Immunology,9 Pharmacology, University of Colorado Health Sciences Center,5 Veterans Administration Medical Center, Denver, Colorado,3 Departments of Microbiology, Pathology, and Parasitology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina4

Received 25 February 2004/ Accepted 13 July 2004

Viral myocarditis is a disease with a high morbidity and mortality. The pathogenesis of this disease remains poorly characterized, with components of both direct virus-mediated and secondary inflammatory and immune responses contributing to disease. Apoptosis has increasingly been viewed as an important mechanism of myocardial injury in noninfectious models of cardiac disease, including ischemia and failure. Using a reovirus murine model of viral myocarditis, we characterized and targeted apoptosis as a key mechanism of virus-associated myocardial injury in vitro and in vivo. We demonstrated caspase-3 activation, in conjunction with terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and annexin binding, in cardiac myocytes after myocarditic viral infection in vitro. We also demonstrated a tight temporal and geographical correlation between caspase-3 activation, histologic injury, and viral load in cardiac tissue after myocarditic viral infection in vivo. Two pharmacologic agents that broadly inhibit caspase activity, Q-VD-OPH and Z-VAD(OMe)-FMK, effectively inhibited virus-induced cellular death in vitro. The inhibition of caspase activity in vivo by the use of pharmacologic agents as well as genetic manipulation reduced virus-induced myocardial injury by 40 to 60% and dramatically improved survival in infected caspase-3-deficient animals. This study indicates that apoptosis plays a critical role in mediating cardiac injury in the setting of viral myocarditis and is the first demonstration that caspase inhibition may serve as a novel therapeutic strategy for this devastating disease.

* Corresponding author. Mailing address: Pediatrics (Infectious Diseases), University of Colorado Health Sciences Center, 4200 East 9th Ave., Box B055, Denver, CO 80262. Phone: (303) 393-4684. Fax: (303) 393-5271. E-mail: roberta.debiasi{at}uchsc.edu.

Journal of Virology, October 2004, p. 11040-11050, Vol. 78, No. 20
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.20.11040-11050.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kawada, J., Zou, P., Mazitschek, R., Bradner, J. E., Cohen, J. I. (2009). Tubacin Kills Epstein-Barr Virus (EBV)-Burkitt Lymphoma Cells by Inducing Reactive Oxygen Species and EBV Lymphoblastoid Cells by Inducing Apoptosis. J. Biol. Chem. 284: 17102-17109 [Abstract] [Full Text]  
  • Kottke, T., Thompson, J., Diaz, R. M., Pulido, J., Willmon, C., Coffey, M., Selby, P., Melcher, A., Harrington, K., Vile, R. G. (2009). Improved Systemic Delivery of Oncolytic Reovirus to Established Tumors Using Preconditioning with Cyclophosphamide-Mediated Treg Modulation and Interleukin-2. Clin. Cancer Res. 15: 561-569 [Abstract] [Full Text]  
  • Qiao, J., Wang, H., Kottke, T., White, C., Twigger, K., Diaz, R. M., Thompson, J., Selby, P., de Bono, J., Melcher, A., Pandha, H., Coffey, M., Vile, R., Harrington, K. (2008). Cyclophosphamide Facilitates Antitumor Efficacy against Subcutaneous Tumors following Intravenous Delivery of Reovirus. Clin. Cancer Res. 14: 259-269 [Abstract] [Full Text]  
  • Carlson, D. L., Maass, D. L., White, J., Sikes, P., Horton, J. W. (2007). Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury. J. Appl. Physiol. 103: 323-330 [Abstract] [Full Text]  
  • Beckham, J. D., Goody, R. J., Clarke, P., Bonny, C., Tyler, K. L. (2007). Novel Strategy for Treatment of Viral Central Nervous System Infection by Using a Cell-Permeating Inhibitor of c-Jun N-Terminal Kinase. J. Virol. 81: 6984-6992 [Abstract] [Full Text]  
  • Samuel, M. A., Morrey, J. D., Diamond, M. S. (2007). Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis. J. Virol. 81: 2614-2623 [Abstract] [Full Text]  
  • Hansberger, M. W., Campbell, J. A., Danthi, P., Arrate, P., Pennington, K. N., Marcu, K. B., Ballard, D. W., Dermody, T. S. (2007). I{kappa}B Kinase Subunits {alpha} and {gamma} Are Required for Activation of NF-{kappa}B and Induction of Apoptosis by Mammalian Reovirus. J. Virol. 81: 1360-1371 [Abstract] [Full Text]  
  • O'Donnell, S. M., Holm, G. H., Pierce, J. M., Tian, B., Watson, M. J., Chari, R. S., Ballard, D. W., Brasier, A. R., Dermody, T. S. (2006). Identification of an NF-{kappa}B-Dependent Gene Network in Cells Infected by Mammalian Reovirus. J. Virol. 80: 1077-1086 [Abstract] [Full Text]  
  • Danthi, P., Hansberger, M. W., Campbell, J. A., Forrest, J. C., Dermody, T. S. (2006). JAM-A-Independent, Antibody-Mediated Uptake of Reovirus into Cells Leads to Apoptosis. J. Virol. 80: 1261-1270 [Abstract] [Full Text]  
  • Fischer, U., Schulze-Osthoff, K. (2005). New Approaches and Therapeutics Targeting Apoptosis in Disease. Pharmacol. Rev. 57: 187-215 [Abstract] [Full Text]  
  • Hoyt, C. C., Richardson-Burns, S. M., Goody, R. J., Robinson, B. A., DeBiasi, R. L., Tyler, K. L. (2005). Nonstructural Protein {sigma}1s Is a Determinant of Reovirus Virulence and Influences the Kinetics and Severity of Apoptosis Induction in the Heart and Central Nervous System. J. Virol. 79: 2743-2753 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»