Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Jun;91(6):2727–2733. doi: 10.1172/JCI116513

Enhanced expression of superoxide dismutase messenger RNA in viral myocarditis. An SH-dependent reduction of its expression and myocardial injury.

H Suzuki 1, A Matsumori 1, Y Matoba 1, B S Kyu 1, A Tanaka 1, J Fujita 1, S Sasayama 1
PMCID: PMC443338  PMID: 8390488

Abstract

The oxygen free radical system has been reported to be activated by influenza virus infection in the lungs. However, the involvement of oxygen radicals in viral myocarditis is still unknown. Captopril, an angiotensin-converting enzyme (ACE) inhibitor and potent free radical scavenger with a sulfhydryl group, was effective for the treatment of viral myocarditis, while enalapril, an ACE inhibitor without a sulfhydryl group, was not effective against acute myocarditis. In this study, we investigated the role of oxygen radicals in the pathogenesis of viral myocarditis and the therapeutic effects of agents with a sulfhydryl group. 4-wk-old BALB/c mice were inoculated with the encephalomyocarditis virus, and treated with captopril or N,2-mercapto-propionyl glycine (MPG), a sulfhydryl-containing amino acid derivative without ACE inhibiting property, from days 4 to 14. On day 14, captopril and MPG significantly improved survival of mice and myocardial injury (necrosis, cellular infiltration, and calcification) in a dose-dependent manner compared with the infected control group. Thus, captopril and MPG were effective for the treatment of virus-induced myocarditis. Furthermore, a striking induction of manganese superoxide dismutase (Mn-SOD) and copper/zinc SOD (Cu/Zn-SOD) mRNAs in infected hearts was found (8-13-fold for Mn-SOD and 4-11-fold for Cu/Zn-SOD) when compared with age-matched uninfected mice hearts. MPG completely inhibited the increase of both mRNAs, even when treatment was started on day 4. Thus, oxygen radicals may play an important role in the pathogenesis of viral myocarditis, and a therapeutic approach by eliminating oxygen radicals seems possible.

Full text

PDF
2727

Images in this article

2730Image
on p.2730
2730Image
on p.2730
2731Image
on p.2731
2731Image
on p.2731

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abelmann W. H., Lorell B. H. The challenge of cardiomyopathy. J Am Coll Cardiol. 1989 May;13(6):1219–1239. doi: 10.1016/0735-1097(89)90293-3. [DOI] [PubMed] [Google Scholar]
  2. Akaike T., Ando M., Oda T., Doi T., Ijiri S., Araki S., Maeda H. Dependence on O2- generation by xanthine oxidase of pathogenesis of influenza virus infection in mice. J Clin Invest. 1990 Mar;85(3):739–745. doi: 10.1172/JCI114499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bewley G. C. cDNA and deduced amino acid sequence of murine Cu-Zn superoxide dismutase. Nucleic Acids Res. 1988 Mar 25;16(6):2728–2728. doi: 10.1093/nar/16.6.2728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carlsson S. M., Denneberg T., Emanuelsson B. M., Kågedal B., Lindgren S. Pharmacokinetics of intravenous 2-mercaptopropionylglycine in man. Eur J Clin Pharmacol. 1990;38(5):499–503. doi: 10.1007/BF02336691. [DOI] [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Doroshow J. H., Locker G. Y., Ifrim I., Myers C. E. Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine. J Clin Invest. 1981 Oct;68(4):1053–1064. doi: 10.1172/JCI110328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eddy L. J., Stewart J. R., Jones H. P., Engerson T. D., McCord J. M., Downey J. M. Free radical-producing enzyme, xanthine oxidase, is undetectable in human hearts. Am J Physiol. 1987 Sep;253(3 Pt 2):H709–H711. doi: 10.1152/ajpheart.1987.253.3.H709. [DOI] [PubMed] [Google Scholar]
  8. Forman H. J., Rotman E. I., Fisher A. B. Roles of selenium and sulfur-containing amino acids in protection against oxygen toxicity. Lab Invest. 1983 Aug;49(2):148–153. [PubMed] [Google Scholar]
  9. Freeman B. A., Crapo J. D. Biology of disease: free radicals and tissue injury. Lab Invest. 1982 Nov;47(5):412–426. [PubMed] [Google Scholar]
  10. Hallewell R. A., Mullenbach G. T., Stempien M. M., Bell G. I. Sequence of a cDNA coding for mouse manganese superoxide dismutase. Nucleic Acids Res. 1986 Dec 9;14(23):9539–9539. doi: 10.1093/nar/14.23.9539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kawai C., Matsumori A., Fujiwara H. Myocarditis and dilated cardiomyopathy. Annu Rev Med. 1987;38:221–239. doi: 10.1146/annurev.me.38.020187.001253. [DOI] [PubMed] [Google Scholar]
  12. Koerner J. E., Anderson B. A., Dage R. C. Protection against postischemic myocardial dysfunction in anesthetized rabbits with scavengers of oxygen-derived free radicals: superoxide dismutase plus catalase, N-2-mercaptopropionyl glycine and captopril. J Cardiovasc Pharmacol. 1991 Feb;17(2):185–191. doi: 10.1097/00005344-199102000-00002. [DOI] [PubMed] [Google Scholar]
  13. Kyu B., Matsumori A., Sato Y., Okada I., Chapman N. M., Tracy S. Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy. Circulation. 1992 Aug;86(2):522–530. doi: 10.1161/01.cir.86.2.522. [DOI] [PubMed] [Google Scholar]
  14. Käriäinen L., Ranki M. Inhibition of cell functions by RNA-virus infections. Annu Rev Microbiol. 1984;38:91–109. doi: 10.1146/annurev.mi.38.100184.000515. [DOI] [PubMed] [Google Scholar]
  15. Lewis S. A., Lee M. G., Cowan N. J. Five mouse tubulin isotypes and their regulated expression during development. J Cell Biol. 1985 Sep;101(3):852–861. doi: 10.1083/jcb.101.3.852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Matsumori A., Crumpacker C. S., Abelmann W. H. Prevention of viral myocarditis with recombinant human leukocyte interferon alpha A/D in a murine model. J Am Coll Cardiol. 1987 Jun;9(6):1320–1325. doi: 10.1016/s0735-1097(87)80472-2. [DOI] [PubMed] [Google Scholar]
  17. Matsumori A., Kawai C. An animal model of congestive (dilated) cardiomyopathy: dilatation and hypertrophy of the heart in the chronic stage in DBA/2 mice with myocarditis caused by encephalomyocarditis virus. Circulation. 1982 Aug;66(2):355–360. doi: 10.1161/01.cir.66.2.355. [DOI] [PubMed] [Google Scholar]
  18. Matsumori A., Kawai C. An experimental model for congestive heart failure after encephalomyocarditis virus myocarditis in mice. Circulation. 1982 Jun;65(6):1230–1235. doi: 10.1161/01.cir.65.6.1230. [DOI] [PubMed] [Google Scholar]
  19. Matsumori A., Suzuki H., Kawai C. Beneficial effects of captopril in coxsackievirus myocarditis. Circulation. 1990 Nov;82(5):1882–1883. [PubMed] [Google Scholar]
  20. Matsumori A., Wang H., Abelmann W. H., Crumpacker C. S. Treatment of viral myocarditis with ribavirin in an animal preparation. Circulation. 1985 Apr;71(4):834–839. doi: 10.1161/01.cir.71.4.834. [DOI] [PubMed] [Google Scholar]
  21. McCord J. M. Free radicals and myocardial ischemia: overview and outlook. Free Radic Biol Med. 1988;4(1):9–14. doi: 10.1016/0891-5849(88)90005-6. [DOI] [PubMed] [Google Scholar]
  22. McCord J. M. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985 Jan 17;312(3):159–163. doi: 10.1056/NEJM198501173120305. [DOI] [PubMed] [Google Scholar]
  23. Mehta J. L., Nicolini F. A., Lawson D. L. Sulfhydryl group in angiotensin converting enzyme inhibitors and superoxide radical formation. J Cardiovasc Pharmacol. 1990 Nov;16(5):847–849. doi: 10.1097/00005344-199011000-00023. [DOI] [PubMed] [Google Scholar]
  24. Mitsos S. E., Askew T. E., Fantone J. C., Kunkel S. L., Abrams G. D., Schork A., Lucchesi B. R. Protective effects of N-2-mercaptopropionyl glycine against myocardial reperfusion injury after neutrophil depletion in the dog: evidence for the role of intracellular-derived free radicals. Circulation. 1986 May;73(5):1077–1086. doi: 10.1161/01.cir.73.5.1077. [DOI] [PubMed] [Google Scholar]
  25. Mitsos S. E., Fantone J. C., Gallagher K. P., Walden K. M., Simpson P. J., Abrams G. D., Schork M. A., Lucchesi B. R. Canine myocardial reperfusion injury: protection by a free radical scavenger, N-2-mercaptopropionyl glycine. J Cardiovasc Pharmacol. 1986 Sep-Oct;8(5):978–988. [PubMed] [Google Scholar]
  26. Pi X. J., Chen X. Captopril and ramiprilat protect against free radical injury in isolated working rat hearts. J Mol Cell Cardiol. 1989 Dec;21(12):1261–1271. doi: 10.1016/0022-2828(89)90672-x. [DOI] [PubMed] [Google Scholar]
  27. Przyklenk K., Kloner R. A. Relationships between structure and effects of ACE inhibitors: comparative effects in myocardial ischaemic/reperfusion injury. Br J Clin Pharmacol. 1989;28 (Suppl 2):167S–175S. doi: 10.1111/j.1365-2125.1989.tb03592.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rezkalla S., Kloner R. A., Khatib G., Khatib R. Beneficial effects of captopril in acute coxsackievirus B3 murine myocarditis. Circulation. 1990 Mar;81(3):1039–1046. doi: 10.1161/01.cir.81.3.1039. [DOI] [PubMed] [Google Scholar]
  29. Sato Y., Maruyama S., Kawai C., Matsumori A. Effect of immunostimulant therapy on acute viral myocarditis in an animal model. Am Heart J. 1992 Aug;124(2):428–434. doi: 10.1016/0002-8703(92)90609-y. [DOI] [PubMed] [Google Scholar]
  30. Schreck R., Rieber P., Baeuerle P. A. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J. 1991 Aug;10(8):2247–2258. doi: 10.1002/j.1460-2075.1991.tb07761.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schwartz L. B., Lawrence C., Thach R. E., Roeder R. G. Encephalomyocarditis virus infection of mouse plasmacytoma cells. II. Effect on host RNA synthesis and RNA polymerases. J Virol. 1974 Sep;14(3):611–619. doi: 10.1128/jvi.14.3.611-619.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tomioka N., Kishimoto C., Matsumori A., Kawai C. Effects of prednisolone on acute viral myocarditis in mice. J Am Coll Cardiol. 1986 Apr;7(4):868–872. doi: 10.1016/s0735-1097(86)80349-7. [DOI] [PubMed] [Google Scholar]
  33. Uma Devi P., Prasanna P. G. Radioprotective effect of combinations of WR-2721 and mercaptopropionylglycine on mouse bone marrow chromosomes. Radiat Res. 1990 Nov;124(2):165–170. [PubMed] [Google Scholar]
  34. Visner G. A., Dougall W. C., Wilson J. M., Burr I. A., Nick H. S. Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1, and tumor necrosis factor. Role in the acute inflammatory response. J Biol Chem. 1990 Feb 15;265(5):2856–2864. [PubMed] [Google Scholar]
  35. Zee-Cheng C. S., Tsai C. C., Palmer D. C., Codd J. E., Pennington D. G., Williams G. A. High incidence of myocarditis by endomyocardial biopsy in patients with idiopathic congestive cardiomyopathy. J Am Coll Cardiol. 1984 Jan;3(1):63–70. doi: 10.1016/s0735-1097(84)80431-3. [DOI] [PubMed] [Google Scholar]
  36. Zimmer G., Evers J. 2-Mercaptopropionylglycine improves aortic flow after reoxygenation in working rat hearts. Basic Res Cardiol. 1988 Jul-Aug;83(4):445–451. doi: 10.1007/BF02005830. [DOI] [PubMed] [Google Scholar]
  37. van Gilst W. H., de Graeff P. A., Wesseling H., de Langen C. D. Reduction of reperfusion arrhythmias in the ischemic isolated rat heart by angiotensin converting enzyme inhibitors: a comparison of captopril, enalapril, and HOE 498. J Cardiovasc Pharmacol. 1986 Jul-Aug;8(4):722–728. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES