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Anti-perforin neutralizing antibody reduces myocardial injury in viral myocarditis

Published online by Cambridge University Press:  14 October 2009

Guo Chun-yan ,
Han Bo ,
Chang Hong ,
Jiang Hong-lei  and
Han Xiu-zhen
Guo Chun-yan
Affiliation:
Cardiology Division, Pediatric Department, Provincal Hospital Affiliated to Shandong University, Shandong, Jinan, China
Han Bo*
Affiliation:
Cardiology Division, Pediatric Department, Provincal Hospital Affiliated to Shandong University, Shandong, Jinan, China
Chang Hong
Affiliation:
Pediatric Department, The Hospital Affiliated to Qingdao University, Shandong, Qingdao, China
Jiang Hong-lei
Affiliation:
Cardiology Division, Pediatric Department, Provincal Hospital Affiliated to Shandong University, Shandong, Jinan, China
Han Xiu-zhen
Affiliation:
Cardiology Division, Pediatric Department, Provincal Hospital Affiliated to Shandong University, Shandong, Jinan, China
*
Correspondence to: Han Bo, Pediatric Devision, Pediatric Department, Provincial Hospital Affiliated to Shandong University, Shandong, Jinan, China. Postal code: 250021; Tel: +86 531 86867000; Fax: +86 531 87917741; E-mail: [email protected]
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Abstract

Aim

To investigate the role of anti-perforin neutralizing antibody in viral myocarditis.

Methods

We divided 45 Balb/c mice randomly into 3 groups, a normal control group, a control group inoculated with coxsackie virus B3, and a group inoculated with anti-perforin neutralizing antibody. The second group was inoculated with 0.15 milliliters coxsackie virus B3, and the third group additionally with 0.1milligrams/kilogram anti-perforin neutralizing antibody at time points of 6 hours and 3 days after infection. Histopathology was performed using haematoxylin and eosin, with apoptosis examined by the terminal transferase-mediated 2′-deoxyuridine 5′-triphosphate-biotin nick, end-labeling method, or Tunel. The expression of caspase-3 in myocardium was investigated by immunohistochemistry and reverse-transcription polymerase chain reaction.

Results

The pathologic score, myocardial viral titers, average percentages of apoptotic cardiomyocytes, expression of active caspase-3 protein and messenger ribonucleic acid in the myocardium of the mice receiving anti-PFP neutralizing antibody therapy were all significantly reduced when compared to values from the group inoculated with coxsackie virus B3. The rates of expression of Caspase-3 and myocardial apoptosis were positively correlated with the scores for myocardial pathology.

Conclusion

Our results suggest that anti- perforin neutralizing antibody can reduce the myocardial damage by blocking the perforin/granzyme pathway, and downregulating the expression of messenger ribonucleic acid and protein of Caspase-3. These approaches may offer promising novel therapeutic strategies for the clinical treatment of viral myocarditis.

Keywords

Micecytotoxic T lymphocytesApoptosisCaspase-3
Type
Original Articles
Information
Cardiology in the Young , Volume 19 , Issue 6 , December 2009 , pp. 601 - 607
Copyright
Copyright © Cambridge University Press 2009

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References

1.Podack, ER. Execution and suicide: cytotoxic lymphocytes enforce Draconian laws through separate molecular pathways. Curr Opin Immunol 1995; 7: 11–16.CrossRefGoogle ScholarPubMed
2.Hassin, D, Fixler, R, Shimoni, Y, et al. Physiological changes induced in cardiac myocytes by cytotoxic T lymphocytes. Am J Physiol 1987; 252: C10–C16.CrossRefGoogle ScholarPubMed
3.Jerome, KR, Sloan, DD, Aubert, M. Measurement of CTL-induced cytotoxicity: the caspase 3 assay. Apoptosis 2003; 8: 563–571.CrossRefGoogle ScholarPubMed
4.Zhang, F, Chu, X, Wang, L, et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2006; 76: 427–431.CrossRefGoogle ScholarPubMed
5.Seko, Y, Shinkai, Y, Kawasaki, A. Evidence of perforin-mediated cardiac myocardiac myocyte injury in acute murine myocarditis caused by coxsackievirus B3. J Pathol 1993; 170: 53–58.CrossRefGoogle Scholar
6.Gupta, M, Greer, P, Mahanty, S, et al. CD8-mediated protection against Ebola virus infection is perforin dependent. Immunology 2005; 174: 4198–4202.Google ScholarPubMed
7.Xiong, DD, Yang, YZ, Hu, Y, Chen, HZ. The relationship between the dynamic changes of Perforin expression level and myocardiac lesion in experimental viral myocarditis. Chinese Journal of Cardiology 1998; 26: 21–23.Google Scholar
8.Xiong, D, Yang, Y, Hu, Y, Chen, H. The role of cytotoxisity effecter mediated by Perforin in mice with viral myocarditis. Journal of Shanghai Medical University 1999; 26: 128–130.Google Scholar
9.White, MK, Amini, S, Khalili, K, Kogan, M, Donaldson, K, Darbinian, N. Development of a bidirectional caspase-3 expression system for the induction of apoptosis. Cancer Biol Ther 2008; 7: 945–954.CrossRefGoogle ScholarPubMed
10.Gobe, G. Identification of apoptosis in kidney tissue sections. Methods Mol Biol 2009; 466: 175–192.CrossRefGoogle ScholarPubMed
11.Lee, SH, Bar-Haim, E, Machlenkin, A, et al. In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL. Cancer Gene Ther 2004; 11: 237–248.CrossRefGoogle ScholarPubMed
12.Cunningham, TD, Jiang, X, Shapiro, DJ. Expression of high levels of human proteinase inhibitor 9 blocks both perforin/granzyme and Fas/Fas ligand-mediated cytotoxicity. Cell Immunol 2007; 245: 32–41.CrossRefGoogle ScholarPubMed
13.Kim, JH, Kang, TH, Noh, KH, et al. Enhancement of dendritic cell-based vaccine potency by anti-apoptotic siRNAs targeting key pro-apoptotic proteins in cytotoxic CD8+ T cell-mediated cell death. Immunol Lett 2009; 122: 58–67.CrossRefGoogle ScholarPubMed
14.Voskoboinik, I, Thia, MC, Fletcher, J, et al. Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491. J Biol Chem 2005; 280: 8426–8434.CrossRefGoogle Scholar
15.Liu, CC, Walsh, CM, Young, JD. Perforin: structure and function. Immunol Today 1995; 16: 194–201.CrossRefGoogle ScholarPubMed
16.Sauer, H, Pratsch, L, Tschopp, J, Bhakdi, S, Peters, R. Functional size of complement and perforin pores compared by confocal laser scanning microscopy and fluorescence microphotolysis. Biochim Biophys Acta 1991; 1063: 137–146.CrossRefGoogle ScholarPubMed
17.Zorc-Pleskovic, R, Alibegović, A, Zorc, M, Milutinović, A, Radovanović, N, Petrović, D. Apoptosis of cardiomyocytes in myocarditis. Folia Biol (Praha) 2006; 52: 6–9.Google ScholarPubMed
18.DeBiasi, RL, Robinson, BA, Sherry, B, et al. Caspase inhibition protects against reovirus-induced myocardial injury in vitro and in vivo. J Virol 2004; 78: 11040–11050.CrossRefGoogle ScholarPubMed
19.Kyto, V, Saraste, A, Saukko, P, et al. Apoptotic cardiomyocyte death in fatal myocarditis. Am J Cardiol 2004; 94: 746–750.CrossRefGoogle ScholarPubMed
20.Saraste, A, Arola, A, Vuorinen, T, et al. Cardiomyocyte apoptosis in experimental coxsackievirus B3 myocarditis. Cardiovasc Pathol 2003; 12: 255–262.CrossRefGoogle ScholarPubMed
21.Cooper, DM, Granville, DJ, Lowenberger, C. The insect caspases. Apoptosis 2009; 14: 247–256.CrossRefGoogle ScholarPubMed
22.Fujikawa, DG, Shinmei, SS, Zhao, S, Aviles, ER Jr. Caspase-dependent programmed cell death pathways are not activated in generalized seizure-induced neuronal death. Brain Res 2007; 1135: 206–218.CrossRefGoogle Scholar
23.Zhang, YB, Ye, YP, Wu, XD, Sun, HX. Astilbotriterpenic acid induces growth arrest and apoptosis in HeLa cells through mitochondria-related pathways and reactive oxygen species (ROS) production. Chem Biodivers 2009; 6: 218–230.CrossRefGoogle ScholarPubMed
24.Ghosh, S, Khazaei, M, Moien Afshari, F, et al. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol 2009; 14.Google Scholar
25.Purevjav, E, Nelson, DP, Varela, JJ, et al. Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy. Cardiovasc Toxicol 2007; 7: 255–263.CrossRefGoogle ScholarPubMed
26.Zapata, JM, Takahashi, R, Salvesen, GS, Reed, JC. Granzyme release and caspase activation in activated human T-lymphocytes. Biol Chem 1998; 273: 6916–6920.CrossRefGoogle ScholarPubMed
27.Galvin, JP, Spaeny-Dekking, LH, Wang, B, Seth, P, Hack, CE, Froelich, CJ. Apoptosis induced by granzyme B-glycosaminoglycan complexes: implications for granule-mediated apoptosis in vivo. Immunol 1999; 162: 5345–5350.Google ScholarPubMed