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Keap1/Nrf2/ARE System Inducers Do Not Increase the Resistance of the Heart to Prolonged Ischemia/Reperfusion

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Abstract

Oxidative stress acts as an important mechanism of myocardial damage during ischemia/reperfusion. To consider the possibility of restoring the redox balance with the help of “indirect” antioxidant effects, the cardioprotective effect of inducers of the Keap1/Nrf2/ARE system was studied when modeling prolonged ischemia/reperfusion in vivo. We used the original synthetic hydrophilic monophenol sodium 3-(3'-tert-butyl-4'-hydroxyphenyl) propylthiosulfonate (TS-13) and reference drug tert-butylhydroquinone (tBHQ). Male Wistar rats received 100 mg/kg of TS-13 solution (with drinking water) or tBHQ (intraperitoneally) daily for 7 days, while animals of the comparison groups received the corresponding solvents. Local ischemia (45 min, occlusion of the left coronary artery) and reperfusion (120 min) of the heart were modeled 1 day after the last drug administration in vivo. During the entire period of ischemia and during reperfusion, an ECG was recorded; at the end of reperfusion, the heart was removed and hypoperfusion and necrosis zones were determined. Changes in the expression of Nfe2l2, Nqo1, hmox1, Gstp1, Rela, and Nfkb2 gene mRNA in myocardial tissue were determined by TaqMan real-time PCR. It was found that the groups of rats treated with TS-13 and tBHQ did not differ from the corresponding control groups in terms of the size of the necrosis zone and the number of rhythm disturbances. Preliminary administration of tBHQ to animals did not change the expression of the studied genes in heart tissue after prolonged ischemia/reperfusion. The administration of TS-13 was accompanied by an increase in the content of transcripts of the gene encoding Nrf2 (by 7.64 times) and Nrf2-driven genes: Nqo1 (6.46 times) and Hmox1 (3.63 times); Gstp1, Rela, and Nfkb2 gene expression did not differ from the corresponding values of the control group; compared to animals treated with tBHQ, Nfe2l2, Nqo1, Hmox1, Rela, Nfkb2 gene expression was 16.23, 4.44, 2.68, 3.17, and 2.64 times larger, respectively. The results obtained cast doubt on the therapeutic significance of the induction of the Keap1/Nrf2/ARE system during prolonged ischemia/reperfusion of the heart.

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ACKNOWLEDGMENTS

The work was performed using the equipment of the “Modern Optical Systems” and “Proteomic Analysis” Centers for Collective Use supported by funding from the Russian Ministry of Education and Science, agreement no. 075-15-2021-691.

Funding

The work was carried out according to state order no. АААА-А20-120013090021-1.

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Authors and Affiliations

  1. Federal Research Center for Fundamental and Translational Medicine, 63011, Novosibirsk, Russia

    P. M. Kozhin, S. E. Khrapov, M. V. Khrapova, L. P. Romakh & E. B. Menshchikova

  2. Research Institute of Cardiology of the Tomsk National Research Medical Center of the Russian Academy of Sciences, 634012, Tomsk, Russia

    A. S. Sementsov

  3. Novosibirsk State Pedagogical University, 630126, Novosibirsk, Russia

    N. V. Kandalintseva

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  1. P. M. Kozhin
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Correspondence to E. B. Menshchikova.

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Kozhin, P.M., Sementsov, A.S., Khrapov, S.E. et al. Keap1/Nrf2/ARE System Inducers Do Not Increase the Resistance of the Heart to Prolonged Ischemia/Reperfusion. Cell Tiss. Biol. 17, 428–435 (2023). https://doi.org/10.1134/S1990519X23040028

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