Calpain Inhibition Protects against Virus-Induced Apoptotic Myocardial Injury
Open Access
- 1 January 2001
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 75 (1), 351-361
- https://doi.org/10.1128/jvi.75.1.351-361.2001
Abstract
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 inhibitorZ-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.Keywords
This publication has 114 references indexed in Scilit:
- Does HIV cause depletion of CD4+ T cells in vivo by the induction of apoptosis?Immunology & Cell Biology, 1999
- Cleavage of the calpain inhibitor, calpastatin, during apoptosisCell Death & Differentiation, 1998
- Bax cleavage is mediated by calpain during drug-induced apoptosisOncogene, 1998
- The expression of Fas Ligand by macrophages and its upregulation by human immunodeficiency virus infection.Journal of Clinical Investigation, 1998
- Involvement of Cellular Proteolytic Machinery in ApoptosisBiochemical and Biophysical Research Communications, 1997
- The Pathogenesis of Postinfectious MyocarditisClinical Immunology and Immunopathology, 1996
- Cytokines in myocarditis and cardiomyopathiesCurrent Opinion in Cardiology, 1996
- Protease activation during apoptosis: Death by a thousand cuts?Cell, 1995
- Autoimmunity in Myocarditis: Models and MechanismsClinical Immunology and Immunopathology, 1993
- Calpain and calpastatinTrends in Biochemical Sciences, 1983