Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Apoptosis and remodeling in adriamycin-induced cardiomyopathy rat model

  • Hong, Young Mi (Department of Pediatrics, Ewha Womans University School of Medicine) ;
  • Lee, Hyeryon (Department of Pediatrics, Ewha Womans University School of Medicine) ;
  • Cho, Min-Sun (Department of Pathology, Ewha Womans University School of Medicine) ;
  • Kim, Kwan Chang (Department of Thoracic and Cardiovascular Surgery, Ewha Womans University School of Medicine)
  • Received : 2017.08.11
  • Accepted : 2017.09.28
  • Published : 2017.11.15
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Abstract

Purpose: The mechanism for the pathogenesis of adriamycin (ADR)-induced cardiomyopathy is not yet known. Different hypotheses include the production of free radicals, an interaction between ADR and nuclear components, and a disruption in cardiac-specific gene expression. Apoptosis has also been proposed as being involved in cardiac dysfunction. The purpose of this study was to determine if apoptosis might play a role in ADR-induced cardiomyopathy. Methods: Male Sprague-Dawley rats were separated into 2 groups: the control group (C group) and the experimental group (ADR 5 mg/wk for 3 weeks through intraperitoneal injections; A group). Echocardiographic images were obtained at week 3. Changes in caspase-3, B-cell leukemia/lymphoma (Bcl)-2, Bcl-2-associated X (Bax), interleukin (IL)-6, tumor necrosis $factor-{\alpha}$, brain natriuretic peptide (BNP), troponin I, collagen 1, and collagen 3 protein expression from the left ventricle tissues of C and A group rats were determined by Western blot. Results: Ascites and heart failure as well as left ventricular hypertrophy were noted in the A group. Ejection fraction and shortening fraction were significantly lower in the A group by echocardiography. The expression of caspase-3, Bax, IL-6, BNP, collagen 1, and collagen 3 were significantly higher in the A group as compared with the C group. Protein expression of Bcl-2 decreased significantly in the A group compared with the C group. Conclusion: ADR induced an upregulation of caspase-3, Bax, IL-6, and collagen, as well as a depression in Bcl-2. Thus, apoptosis and fibrosis may play an important role in ADR-induced cardiomyopathy.

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References

  1. Booser DJ, Hortobagyi GN. Anthracycline antibiotics in cancer therapy. Focus on drug resistance. Drugs 1994;47:223-58. https://doi.org/10.2165/00003495-199447020-00002
  2. Wu S, Ko YS, Teng MS, Ko YL, Hsu LA, Hsueh C, et al. Adriamycininduced cardiomyocyte and endothelial cell apoptosis: in vitro and in vivo studies. J Mol Cell Cardiol 2002;34:1595-607. https://doi.org/10.1006/jmcc.2002.2110
  3. Singal PK, Deally CM, Weinberg LE. Subcellular effects of adriamycin in the heart: a concise review. J Mol Cell Cardiol 1987;19:817-28. https://doi.org/10.1016/S0022-2828(87)80392-9
  4. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339:900-5. https://doi.org/10.1056/NEJM199809243391307
  5. Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 1999;57:727-41. https://doi.org/10.1016/S0006-2952(98)00307-4
  6. Doroshow JH. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 1983;43:460-72.
  7. Siveski-Iliskovic N, Kaul N, Singal PK. Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation 1994;89:2829-35. https://doi.org/10.1161/01.CIR.89.6.2829
  8. Hong YM, Kim HS, Yoon HR. Serum lipid and fatty acid profiles in adriamycin-treated rats after administration of L-carnitine. Pediatr Res 2002;51:249-55. https://doi.org/10.1203/00006450-200202000-00020
  9. Gosalvez M, van Rossum GD, Blanco MF. Inhibition of sodiumpotassium-activated adenosine 5'-triphosphatase and ion transport by adriamycin. Cancer Res 1979;39:257-61.
  10. Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012;52:1213-25. https://doi.org/10.1016/j.yjmcc.2012.03.006
  11. Suliman HB, Carraway MS, Ali AS, Reynolds CM, Welty-Wolf KE, Piantadosi CA. The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J Clin Invest 2007;117:3730-41.
  12. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM. Apoptosis in human acute myocardial infarction. Circulation 1997;95:320-3. https://doi.org/10.1161/01.CIR.95.2.320
  13. Nitobe J, Yamaguchi S, Okuyama M, Nozaki N, Sata M, Miyamoto T, et al. Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes. Cardiovasc Res 2003;57:119-28. https://doi.org/10.1016/S0008-6363(02)00646-6
  14. Liu B, Bai QX, Chen XQ, Gao GX, Gu HT. Effect of curcumin on expression of survivin, Bcl-2 and Bax in human multiple myeloma cell line. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2007;15:762-6.
  15. Kumar D, Kirshenbaum LA, Li T, Danelisen I, Singal PK. Apoptosis in adriamycin cardiomyopathy and its modulation by probucol. Antioxid Redox Signal 2001;3:135-45. https://doi.org/10.1089/152308601750100641
  16. Miyata S, Takemura G, Kosai K, Takahashi T, Esaki M, Li L, et al. Anti-Fas gene therapy prevents doxorubicin-induced acute cardiotoxicity through mechanisms independent of apoptosis. Am J Pathol 2010;176:687-98. https://doi.org/10.2353/ajpath.2010.090222
  17. Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev 2007;87:1285-342. https://doi.org/10.1152/physrev.00012.2007
  18. Goetzenich A, Hatam N, Zernecke A, Weber C, Czarnotta T, Autschbach R, et al. Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig. J Heart Lung Transplant 2009;28:1087-93. https://doi.org/10.1016/j.healun.2009.06.025
  19. Choy JC, Granville DJ, Hunt DW, McManus BM. Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J Mol Cell Cardiol 2001;33:1673-90. https://doi.org/10.1006/jmcc.2001.1419
  20. Arola OJ, Saraste A, Pulkki K, Kallajoki M, Parvinen M, Voipio-Pulkki LM. Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 2000;60:1789-92.
  21. Zhang J, Clark JR Jr, Herman EH, Ferrans VJ. Doxorubicin-induced apoptosis in spontaneously hypertensive rats: differential effects in heart, kidney and intestine, and inhibition by ICRF-187. J Mol Cell Cardiol 1996;28:1931-43. https://doi.org/10.1006/jmcc.1996.0186
  22. Nakamura T, Ueda Y, Juan Y, Katsuda S, Takahashi H, Koh E. Fasmediated apoptosis in adriamycin-induced cardiomyopathy in rats: In vivo study. Circulation 2000;102:572-8. https://doi.org/10.1161/01.CIR.102.5.572
  23. Rossig L, Haendeler J, Mallat Z, Hugel B, Freyssinet JM, Tedgui A, et al. Congestive heart failure induces endothelial cell apoptosis: protective role of carvedilol. J Am Coll Cardiol 2000;36:2081-9. https://doi.org/10.1016/S0735-1097(00)01002-0
  24. Youn HJ, Kim HS, Jeon MH, Lee JH, Seo YJ, Lee YJ, et al. Induction of caspase-independent apoptosis in H9c2 cardiomyocytes by adriamycin treatment. Mol Cell Biochem 2005;270:13-9. https://doi.org/10.1007/s11010-005-2541-2
  25. Bruynzeel AM, Abou El Hassan MA, Torun E, Bast A, van der Vijgh WJ, Kruyt FA. Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells. Br J Cancer 2007;96:450-6. https://doi.org/10.1038/sj.bjc.6603598
  26. Abbate A, Biondi-Zoccai GG, Bussani R, Dobrina A, Camilot D, Feroce F, et al. Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure. J Am Coll Cardiol 2003;41:753-60. https://doi.org/10.1016/S0735-1097(02)02959-5
  27. Panjrath GS, Jain D. Monitoring chemotherapy-induced cardiotoxicity: role of cardiac nuclear imaging. J Nucl Cardiol 2006;13:415-26. https://doi.org/10.1016/j.nuclcard.2006.03.002
  28. Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR, et al. The effect of dexrazoxane on myocardial injury in doxorubicintreated children with acute lymphoblastic leukemia. N Engl J Med 2004;351:145-53. https://doi.org/10.1056/NEJMoa035153
  29. Pulkki KJ. Cytokines and cardiomyocyte death. Ann Med 1997;29:339-43. https://doi.org/10.3109/07853899708999358
  30. Cesselli D, Jakoniuk I, Barlucchi L, Beltrami AP, Hintze TH, Nadal-Ginard B, et al. Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res 2001;89:279-86. https://doi.org/10.1161/hh1501.094115

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