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
- 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
- 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
- Elliott P. Cardiomyopathy. Diagnosis and management of dilated cardiomyopathy. Heart. 2000;84:106-12.
CrossRef
PubMed PubMedCentral
- 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
- Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of anthracyclines. Front Cardiovascul Med. 2020;7:26-4.
CrossRef
PubMed PubMedCentral
- Volkova M, Russell R. Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011;7:214-20.
CrossRef
PubMed PubMedCentral
- Zhou S, Palmeira CM, Wallace KB. Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett. 2001;121:151-7.
CrossRef
PubMed
- Wallace KB, Sardao VA, Oliveira PJ. Mitochondrial determinants of doxorubicin-induced cardiomyopathy. Circ Res. 2020;126:926-41.
CrossRef
PubMed PubMedCentral
- 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.
- 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
- 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.
- 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
- 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
- Halestrap AP. What is the mitochondrial permeability transition pore? J Mol Cell Cardiol. 2009;46:821-31.
CrossRef
PubMed
- Karupu VY. Electron microscopy. K.:Higher school. 1984;208-10.
- Weibel ER. Morphometry of human lungs.K.:Medicine. 1970;170-2.
- 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
- 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.
- Rozova KV. Structurally determined mitochondrial response to hypoxia and neurodegeneration. Kyiv: Znannya. 2019. [Ukrainian].
- 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
- 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
- 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
- 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
- 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
- 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
- Periasamy M. Calcineurin and the heartbeat, an evolving story. J Mol Cell Cardiol. 2002;34:259-62.
CrossRef
PubMed
|