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ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2023; 69(6): 3-14


MITOCHONDRIAL DYSFUNCTION IN ACUTE CARDIOTOXIC EFFECT OF DOXORUBICIN IN ADULT RATS

M.V. Denysova, N.A. Strutynska, L.A. Mys, Yu.P. Korkach, K.V. Rozova, V.F. Sagach

    Bogomoletz Institute of Physiology of the National Academy of Sciences of Ukraine, Kyiv, Ukraine
DOI: https://doi.org/10.15407/fz69.06.003


Abstract

Doxorubicin is a potent cytotoxic antibiotic that is the most widely prescribed in the world and is effective against a wide range of cancers. At the same time, the cardiotoxic effects of this drug often require discontinuation of treatment before the effect is achieved. Mitochondria are important mediators of cellular life, and cardiomyocyte death due to mitochondrial mechanisms of internal killing is the basis of many heart diseases. The aim of the study was to investigate the effects of short-term doxorubicin administration on Ca2+-induced opening of the nonspecific mitochondrial permeability transition pore (mPTP) in the heart of adult rats. To reproduce and evaluate acute cardiotoxicity in rats, which is the main complication in patients taking doxorubicin, a short-term doxorubicin cardiomyopathy model was used. A comparative ultrastructural study of myocardial tissues was performed at total cumulative doses of doxorubicin of 8, 13 and 15 mg/kg administered intraperitoneally and spread over two days. It was shown that the drug caused damage and death of the myofibrillar apparatus, mitochondria and cardiomyocytes and exhibited a dose-dependent effect. Therefore, further experiments were carried out at the most indicative dose, namely 15 mg/kg. We have shown that the content of reactive oxygen species in the heart mitochondria, namely, •O2-, Н2О2, •ОН, increased after doxorubicin administration by 10.5, 5.3 and 3.4 times, respectively, indicating a significant increase in free radical processes. It is important that at the same time, the content of endogenous H2S decreased by 2.6 times. This activated mPTP opening in the rat heart: the amplitude of spontaneous swelling doubled, Ca2+-induced swelling increased by 53% compared to the control, and an increase in mPTP sensitivity to Ca2+ was observed at all applied concentrations. Thus, the acute cardiotoxic effect of doxorubicin resulted in the induction of mPTP opening, which led to mitochondrial and cardiomyocyte death.

Keywords: doxorubicin; nonspecific mitochondrial permeability transition pore; mitochondria; cardiomyocytes; cardiomyopathy

References

  1. Tarr M, van Helden PD. Inhibition of transcription by adriamycin is a consequence of the loss of negative superhelicity in DNA mediated by topoisomerase II. Mol Cell Biochem. 1990;93:141-6. CrossRef PubMed
  2. Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF. Identification of the molecular basis of doxorubicininduced cardiotoxicity. Nat Med. 2012;18:1639-42. CrossRef PubMed
  3. Elliott P. Cardiomyopathy. Diagnosis and management of dilated cardiomyopathy. Heart. 2000;84:106-12. CrossRef PubMed PubMedCentral
  4. Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Nair N, Gongora E. Heart failure in chemotherapyrelated cardiomyopathy: Can exercise make a difference? BBA Clin. 2016;6:69-75. CrossRef PubMed PubMedCentral
  5. Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of anthracyclines. Front Cardiovascul Med. 2020;7:26-4. CrossRef PubMed PubMedCentral
  6. Volkova M, Russell R. Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011;7:214-20. CrossRef PubMed PubMedCentral
  7. Zhou S, Palmeira CM, Wallace KB. Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett. 2001;121:151-7. CrossRef PubMed
  8. Wallace KB, Sardao VA, Oliveira PJ. Mitochondrial determinants of doxorubicin-induced cardiomyopathy. Circ Res. 2020;126:926-41. CrossRef PubMed PubMedCentral
  9. Nakahara T, Petrov A, Tanimoto T, Chaudhry F, Narula N, Seshan SV, Mattis JA, Pak KY, Sahni G, Bhardwaj A, Sengupta PP, Tiersten A, Strauss HW, Narula J. Molecular imaging of apoptosis in cancer therapy related cardiac dysfunction before LVEF reduction. JACC Cardiovascul Imag. 2018;S1936-878X(18):30005-6.
  10. Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: Alterations produced by doxorubicin. J Clin Invest. 1980;65:128-35. CrossRef PubMed PubMedCentral
  11. Kaiserova H, Simunek T, Sterba M, den Hartog GJ, Schroterova L, Popelova O, Gersl V, Kvasnickova E, Bast A. New iron chelators. Circ Res. 2022;23(5):11-8.
  12. Strutynska N, Goshovska Y, Mys L, Strutynskyi R, Luchkova A, Fedichkina R, Okhai I, Korkach Y, Sagach V. Glutathione restores the mitochondrial redox status and improves the function of the cardiovascular system in old rats. Front Physiol. 2023 Jan 9;13:1093388. CrossRef PubMed PubMedCentral
  13. Montaigne D, Marechal X, Preau S, Baccouch R, Modine T, Fayad G,Lancel S, Neviere R. Doxorubicin induces mitochondrial permeability transition and contractile dysfunction in the human myocardium. Mitochondrion. 2011;11:22-6. CrossRef PubMed
  14. Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol. 2009;46:821-31. CrossRef PubMed
  15. Karupu VY. Electron microscopy. K.:Higher school. 1984;208-10.
  16. Weibel ER. Morphometry of human lungs.K.:Medicine. 1970;170-2.
  17. Strutynska N, Strutynskyi R, Mys L, Luchkova A, Korkach Y, Goshovska Y, Sagach V. Exercise restores endogenous H2S synthesis and mitochondrial function in the heart of old rats. Eur J Cell Invest. 2022;412:1-24. CrossRef PubMed
  18. Sagach VF, Vavilova GL, Strutynska NA, Rudyk OV. The aging increase in the sensitivity of the mitochondrial permeability transition pore opening to inductors in rat heart. Fiziol Zh. 2004;50(2):49-63.
  19. Rozova KV. Structurally determined mitochondrial response to hypoxia and neurodegeneration. Kyiv: Znannya. 2019. [Ukrainian].
  20. Kuropka P, Dobrzyński M, Gamian A, GostomskaPampuch K, Kuryszko J, Całkosiński I. Effect of glucocorticoids on ultrastructure of myocardial muscle in the course of experimentally induced acute myocardial ischemia. Biomed Res Int. 2017;210:84-97. CrossRef PubMed PubMedCentral
  21. Tokarska-Schlattner M, Zaugg M, da Silva R, Lucchinetti E, Schaub MC, Wallimann T, Schlattner U. Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply. Am J Physiol. 2005;289:H37-H47. CrossRef PubMed
  22. Strutyns'ka N, Semenykhina O, Chorna S, Vavilova H, Sahach V. Hydrogen sulfide inhibits Ca2+-induced mitochondrial permeability transition pore opening in adult and old rat heart. Fiziol Zh. 2011; 57(6): 3-14. CrossRef
  23. David J, Polhemus, John W, Javed B, David J. The cardioprotective actions of hydrogen sulfide in acute myocardial infarction and heart failure. Hindawi Publ Corp Sci Vol. 2014; 768607: 8. CrossRef PubMed PubMedCentral
  24. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA. Caspase-12 mediates endoplasmic-reticulumspecific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000; 403:98-103. CrossRef PubMed
  25. Argaud L, Gateau-Roesch O, Muntean D, Chalabreysse L, Loufouat J, Robert D, Ovize M. Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol. 2005;38:367-74. CrossRef PubMed
  26. Periasamy M. Calcineurin and the heartbeat, an evolving story. J Mol Cell Cardiol. 2002;34:259-62. CrossRef PubMed

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