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Cardioprotective Effect of 2-Ethyl-3-Hydroxy-6-Methylpyridinium 2-Nitroxysuccinate Against Adrenaline/Hydrocortisone-Induced Myocardial Ischemia in Mice: Modulation of Free-Radical Processes in Biomembranes and Monoamine Oxidase A Activity

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Abstract

Oxidative stress (OS) plays a key role in the development of cardiovascular diseases (CVD) in three major ways: reactive oxygen species (ROS)-induced reduction of nitric oxide (NO) bioavailability, ROS-induced inflammation and ROS-induced mitochondrial dysfunction. Oxidation of lipid molecules under the action of ROS leads to damage to membrane structures, changes the functioning of membrane-bound enzymes, and impairs membrane permeability and stability. An increase in OS results in the occurrence of endothelial dysfunction and drug tolerance, side effects, requiring discontinuation of drugs. All of these are significant problems of cardiotherapy. Therefore, the search for new alternative NO donors continues. The present research was aimed at studying the protective effect of 2-ethyl-3-hydroxy-6-methylpyridinium 2-nitroxysuccinate (NS) on the cardiovascular system on mouse myocardial ischemia (MI) model. The NS hybrid molecule includes a synthetic vitamin B6 analog 2-ethyl-3-hydroxy-6-methylpyridine (an antioxidant) and 2-nitroxysuccinic acid (a source of nitric oxide). Using the electron paramagnetic resonance (EPR) method and biochemical methods, we showed that the pronounced ability of NS to release NO is favorably combines with the capacity to prevent OS due to mechanisms such as suppression of the lipid peroxidation (LPO) process, antiradical activity and inhibition of the mitochondrial membrane-bound monoamine oxidase A (MAO-A). Using histological methods, we established that the administration of NS (10 mg/kg, i.p.) reduces the number of ischemic fibers and protects cardiomyocytes against ischemia injury. Thus, the complex protective effect allows us to consider NS as an alternative NO donor and a candidate for the development of a new pharmaceutical agent for the treatment of CVD.

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Abbreviations

ALT:

alanine aminotransferase activity

AST:

serum aspartate aminotransferase

CVD:

cardiovascular diseases

Cys:

cysteine

DETA-NONOate:

2,2’-(Hydroxynitrosohydrazino)bis-ethanamine

EDTA:

ethylenediaminetetraacetic acid

eNOS:

endothelial nitric oxide synthase

EPR:

electron paramagnetic resonance

H&E:

hematoxylin and eosin

Hb:

deoxyhemoglobin

HBFP:

haematoxylin-basic fuchsin-picric acid

i.p:

intraperitoneally

IHD:

ischemic heart disease

LD50:

median lethal dose

LPO:

lipid peroxidation

MAO-A:

monoamine oxidase A

MI:

myocardial ischemia

NO:

nitric oxide

NS:

2-ethyl-3-hydroxy-6-methylpyridinium 2-nitroxysuccinate

OS:

oxidative stress

PBS:

phosphate-buffered saline

s.c:

subcutaneous

TBARS:

TBA-reactive substances

tBuOOH:

tert-Butyl hydroperoxide

TCA:

trichloroacetic acid

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Acknowledgements

The authors are grateful to S. Ya. Gadomsky (Researcher, FRC PCP MC RAS) and A. B. Eremeev (engineer, FRC PCP MC RAS) for synthesis and provision of NS.

Funding

The work was supported by the Ministry of Science and Higher Education of the Russian Federation, the State Task № АААА-А19-119071890015-6, using the equipment of the Medicinal Chemistry Research and Education Center of Moscow region State University.

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Authors and Affiliations

  1. Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences (FRC PCP MC RAS), Academician Semenov avenue 1, Chernogolovka, Moscow Region, 142432, Russia

    Irina I. Faingold, Anastasia V. Smolina, Yulia V. Soldatova, Darya A. Poletaeva, Anastasia A. Balakina, Tatyana E. Sashenkova, Uguljan Yu. Allayarova, Tatyana R. Prikhodchenko, Svetlana V. Blokhina, David A. Areshidze, Vladislav N. Varfolomeev, Denis V. Mishchenko & Raisa A. Kotelnikova

  2. Avtsyn Research Institute of Human Morphology of Federal state budgetary scientific institution “Petrovsky National Research Centre of Surgery”, 3 Tsyurupy Street, Moscow, 117418, Russia

    Lyudmila A. Makartseva & David A. Areshidze

  3. Medicinal Chemistry Research and Education Center, Moscow Region State University, 24 Vera Voloshina Street, Mytishchi, Moscow Region, 141014, Russia

    Denis V. Mishchenko

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  1. Irina I. Faingold
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  2. Anastasia V. Smolina
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Contributions

All authors contributed to the study conception and design. Conceptualization, methodology: R.A.K., I.I.F., D.A.A., T.E.S., U.Y.A., S.V.B.; formal analysis and experimental investigation: I.I.F., D.A.A., A.V.S., Y.V.S., L.A.M., A.A.B., D.A.P., T.R.P., V.N.V.; writing—original draft preparation: A.V.S., D.V.M., D.A.A., D.A.P.; writing—review and editing: I.I.F., A.V.S., R.A.K.; supervision: I.I.F., R.A.K

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Correspondence to Irina I. Faingold.

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The work has been carried out in accordance with the European Directive 2010/63/EU and was approved by the Ethical Committee of FRC PCP MC RAS (Approval No 22/3 from 13 December 2022).

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Faingold, I.I., Smolina, A.V., Soldatova, Y.V. et al. Cardioprotective Effect of 2-Ethyl-3-Hydroxy-6-Methylpyridinium 2-Nitroxysuccinate Against Adrenaline/Hydrocortisone-Induced Myocardial Ischemia in Mice: Modulation of Free-Radical Processes in Biomembranes and Monoamine Oxidase A Activity. Cell Biochem Biophys 82, 235–245 (2024). https://doi.org/10.1007/s12013-023-01203-7

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