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0225U005069,
(0124U001684)
,
Redox-dependent mechanisms of changes in cardiovascular function in aging and doxorubicin-induced heart failure.
Мітохондіальні механізми розвитку DOX-індукованої серцевої недостатності у щурів та роль АТФ-залежних калієвих каналів, глутатіону та газотрансміттерів.
Sagach Vadym F., д.мед.н.
24-12-2025
Bogomolets Institute of Physiology of the National Academy of Sciences of Ukraine
The aim of this study is to investigate redox-dependent mechanisms of changes in cardiovascular function in aging and doxorubicin(DOX)-induced heart failure. Particular attention will be paid to DOX-induced mitochondrial dysfunction in the rat heart and the role of ATP-sensitive potassium channels (KATP channels) as well as endogenous antioxidants - glutathione and gas transmitters. It is known that KATP channels are universal regulators of cellular functions and metabolism, which determines their key role in defense mechanisms. The work will investigate the functioning of the cardiovascular system in experimental DOX-induced heart failure (cardiotoxicity) in rats and in conditions of activation of endogenous defense mechanisms. Also, the search for antioxidant agents for the correction of cardiac disorders of different genesis (aging, DOX-induced heart failure) will be carried out, in particular the effect of KATP channel openers and new nanomaterials as potential antioxidants, etc. The role of melatonin deficiency (hypomelatoninemia) in the development of cardiac mitochondrial dysfunction will be established and the functional state of the cardiovascular system under conditions of inhibition of endogenous melatonin synthesis will be studied.
Doxorubicin (DOX) is a highly effective antitumor antibiotic, the clinical use of which is limited by cardiotoxicity. A key role in cardiomyocyte death is played by mitochondrial dysfunction caused by the opening of the mitochondrial permeability transition pore (mPTP) and oxidative stress. The aim of this stage of the work was to study the effect of DOX on the functioning of heart mitochondria and to evaluate the protective action of the KATP channel activator flocalin. The model of acute heart injury was reproduced by DOX administration (total dose of 15 mg/kg). The experimental group received flocalin (total dose of 12.5 mg/kg) against the background of DOX administration. DOX administration to animals led to a sharp increase in free radical processes in heart mitochondria. The generation rate of superoxide anion (•O2-) increased by an order of magnitude (10.5-fold), hydroxyl radical (•ОН) – by 3.4 times, and hydrogen peroxide (H2O2) content – by 5.3 times compared to the control. This was accompanied by the depletion of the endogenous gasotransmitter hydrogen sulfide. In animals with DOX-induced heart injury, mPTP induction was revealed: the amplitude of spontaneous mitochondrial swelling increased twofold, and Ca2+-induced swelling – by 53%, indicating the progression of mitochondrial dysfunction. The KATP channel activator Flocalin exhibited a pronounced antioxidant and mitoprotective effect, effectively preventing the generation of reactive oxygen species (ROS) as well as DOX-dependent mitochondrial dysfunction. Thus, the mechanisms of DOX-induced heart injury development are associated with a critical increase in ROS production, hydrogen sulfide deficiency, and the induction of mPTP opening. Activation of KATP channels exhibits pronounced membrane-stabilizing, antioxidant, and mitoprotective effects, preventing the death of mitochondria and, likely, cardiomyocytes.
Yuliia V. Hoshovska
Yuliia P. Korkach
Ilina Tetiana A.
V.F. Sahach
Nataliia A. Strutynska
Lidiia A. Mys
Iryna Y. Okhai
Yuliya O. Bubnova
Maiia V. Denysova
2025-12-24
Updated: 2025-12-25
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