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Profile of Molecular Markers of Cardiac Fibrosis in Rats Exposed to Different Doxorubicin Doses

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Abstract

The study is devoted to investigating the profile of molecular markers of fibrosis in Wistar rats exposed to different doses of doxorubicin. Forty male Wistar rats weighing 260 ± 19 g were divided into 4 groups: one control and three experimental groups corresponding to different cumulative doses of doxorubicin (5, 10, 15 mg/kg, i.p.), each administered 6 times every third day. After reaching cumulative doses, animals were under observation for 2 months. At the end of the observation period, rat hearts were taken for molecular and morphological studies. Histological, echocardiographic and molecular analyses revealed doxorubicin-induced dose-dependent lesions in the left ventricular myocardium. In all three experimental groups, TGF-β expression level was indistinguishable from the control. At the same time, animals treated with a maximum cumulative dose of doxorubicin (15 mg/kg) retained increased expression of type I and II collagen, ET-1, FGF4 and TNF-α, which suggested, on the one hand, an incomplete formation of fibrous connective tissue and, on the other hand, an active involvement of these markers of cardiac fibrosis in inflammatory processes against the background of pronounced cardiotoxic effect of the chemotherapy drug. In animals administered with a medium doxorubicin dose (10 mg/kg), expression levels of the above molecular markers did not differ from those in the control group, whereas the treatment with a minimum dose (5 mg/kg) led to a decrease in the expression of type I and II collagen, ET-1 and TNF-α, but an increase in FGF4 expression levels.

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Funding

This study was supported by the governmental assignment of the Ministry of Health of the Russian Federation (Creation of new drugs for the treatment and prevention of doxorubicin-induced cardiomyopathy).

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Authors and Affiliations

  1. Almazov National Medical Research Centre, Ministry of Health of the Russian Federation, St. Petersburg, Russia

    E. Yu. Podyacheva, T. V. Shmakova, D. D. Andreeva, R. I. Toropov, Yu. V. Cheburkin, M. S. Danilchuk, M. O. Martynov & Ya. G. Toropova

Authors
  1. E. Yu. Podyacheva
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  2. T. V. Shmakova
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  3. D. D. Andreeva
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  4. R. I. Toropov
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  5. Yu. V. Cheburkin
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  6. M. S. Danilchuk
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  7. M. O. Martynov
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  8. Ya. G. Toropova
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Contributions

Conceptualization and experimental design (Ya.G.Т., Е.Yu.P.); data collection (Е.Yu.P., Т.V.Sh., D.D.A., M.S.D., R.I.Т., Yu.V.Ch., М.О.М., S.А.O.); data analysis and interpretation (Е.Yu.P., Т.V.Sh., D.D.А.); writing and editing the manuscript (Е.Yu.P., Yu.V.Ch., Ya.G.Т.).

Corresponding author

Correspondence to E. Yu. Podyacheva.

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COMPLIANCE WITH ETHICAL STANDARDS

All applicable international, national and/or institutional principles of animal care and use were followed. The experimental protocol was approved by the Bioethics Committee at the Almazov Scientific Research Centre of the Ministry of Health of the Russian Federation, IACUC (protocol No. 20-09PZ#V2).

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

Additional information

Translated by A. Polyanovsky

Russian Text © The Author(s), 2023, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2023, Vol. 59, No. 2, pp. 121–130https://doi.org/10.31857/S0044452923020043.

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Podyacheva, E.Y., Shmakova, T.V., Andreeva, D.D. et al. Profile of Molecular Markers of Cardiac Fibrosis in Rats Exposed to Different Doxorubicin Doses. J Evol Biochem Phys 59, 359–368 (2023). https://doi.org/10.1134/S0022093023020059

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