actabiomedicaActa Biomedica ScientificaActa Biomedica Scientifica2541-94202587-9596Scientific Centre for Family Health and Human Reproduction Problems10.29413/ABS.2024-9.5.12actabiomedica-5040Research ArticleКАРДИОЛОГИЯCARDIOLOGYЛейкоцит как адекватная модель изучения характера изменений энергетического обмена в клетках сердца под влиянием кардиоцитопротекторов при ишемии миокардаLeukocyte as an adequate model for studying changes in energy metabolism in heart cells under the influence of cardiocytoprotectors in myocardial ischemiahttps://orcid.org/0000-0002-0032-0341ХохловА. Л.KhokhlovA. L.

150000, г. Ярославль, ул. Революционная, 5

Alexander L. Khokhlov – Dr. Sc. (Med.), Member of the RAS, Professor, Head of the Department of Pharmacology and Clinical Pharmacology, Rector

Revolyutsionnaya str. 5, Yaroslavl 150000

al460935@yandex.ruhttps://orcid.org/0000-0003-2496-5870РомащенкоО. В.RomashchenkoO. V.

150000, г. Ярославль, ул. Революционная, 5

308015, г. Белгород, ул. Победы, 85

Olesya V. Romashchenko – Cand. Sc. (Med.), Docent, Associate Professor at the Department of Pharmacology and Clinical Pharmacology

Pobedy str. 85, Belgorod 308015

RomashenkoOV@gmail.comhttps://orcid.org/0000-0001-5622-6525РумбештВ. В.RumbeshtV. V.

308015, г. Белгород, ул. Победы, 85

Vadim V. Rumbesht – Cand. Sc. (Techn.), Docent, Associate Professor at the Department of Mathematical and Software Information Systems

Pobedy str. 85, Belgorod 308015

rumbesht@bsu.edu.ruhttps://orcid.org/0000-0002-4031-6267ЯкунченкоТ. И.YakunchenkoT. I.

308015, г. Белгород, ул. Победы, 85

Tatyana I. Yakunchenko – Dr. Sc. (Med.), Professor, Head of the Department of Propaedeutics of Internal Medicine and Clinical Information Technologies of the Medical Institute

Pobedy str. 85, Belgorod 308015

yakunchenko@bsu.edu.ruhttps://orcid.org/0000-0002-4031-6267ЖернаковаН. И.ZhernakovaN. I.

308015, г. Белгород, ул. Победы, 85

Nina I. Zhernakova – Dr. Sc. (Med.), Professor, Head of the Department of Family Medicine of the Medical Institute

Pobedy str. 85, Belgorod 308015

zhernakova@bsu.edu.ruhttps://orcid.org/0000-0001-7648-0774ЗакироваЛ. Р.ZakirovaL. R.

308015, г. Белгород, ул. Победы, 85

Lyudmila R. Zakirova – Candidate of Biological Sciences, Associate Professor, Associate Professor at the Department of Biochemistry of the Medical Institute

Pobedy str. 85, Belgorod 308015

zhernakova@bsu.edu.ruКукесВ. Г.KukesV. G.

119048, г. Москва, ул. Трубецкая, 8, стр. 2

Vladimir G. Kukes – Dr. Sc. (Med.), Professor, Academician of the Russian Academy of Sciences, Honorary Professor of the Department of Clinical Pharmacology and Propaedeutics of Internal Diseases

Trubetskaya str. 8, build. 2, Moscow 119048

ФГБОУ ВО «Ярославский государственный медицинский университет» Минздрава РоссииYaroslavl State Medical UniversityФГБОУ ВО «Ярославский государственный медицинский университет» Минздрава России; ФГАОУ ВО «Белгородский государственный национальный исследовательский университет»Yaroslavl State Medical University; Belgorod State National Research UniversityФГАОУ ВО «Белгородский государственный национальный исследовательский университет»Belgorod State National Research UniversityФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский Университет)I.M. Sechenov First Moscow State Medical University (Sechenov University)20242211202495114121Copyright © Хохлов А.Л., Ромащенко О.В., Румбешт В.В., Якунченко Т.И., Жернакова Н.И., Закирова Л.Р., Кукес В.Г., 20242024Хохлов А.Л., Ромащенко О.В., Румбешт В.В., Якунченко Т.И., Жернакова Н.И., Закирова Л.Р., Кукес В.Г.Khokhlov A.L., Romashchenko O.V., Rumbesht V.V., Yakunchenko T.I., Zhernakova N.I., Zakirova L.R., Kukes V.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.actabiomedica.ru/jour/article/view/5040

Целью данного исследования явилось определение возможности изучения характера влияния кардиоцитопротекторов на энергетический обмен в кардиомиоцитах на модели лейкоцитов периферической крови человека. Материалы и методы. Шестьдесят крыс линии Вистар были разделены на группы: 1) интактные крысы; 2) крысы с экспериментальной ишемией миокарда; 3) крысы с ишемией миокарда, которым вводили кардиоцитопротектор – триметазидин, 4) мельдоний, 5) цитофлавин и 6) этоксидол. Животных выводили из эксперимента через 10 суток после введения препаратов методом декапитации. Активность пируватдегидрогеназы и цитратсинтазы определяли в митохондриях гомогенатов миокарда и в митохондриях лейкоцитов спектрофотометрическими методами. Результаты. При моделировании ишемии миокарда выявлено снижение активности пируватдегидрогеназы и цитратсинтазы в кардиомиоцитах и в лейкоцитах. Введение кардиоцитопротекторов приводило к активации этих ферментов как в клетках сердца, так и в лейкоцитах крови. Получены прямые положительные корреляции между активностью пируватдегидрогеназы в митохондриях кардиомиоцитов и в митохондриях лейкоцитов (r = 0,811; p < 0,0001); между активностью цитратсинтазы в митохондриях кардиомиоцитов и в митохондриях лейкоцитов (r = 0,909; p < 0,0001). Заключение. Изменения энергетического обмена в лейкоцитах крови под влиянием цитопротекторов отражают аналогичные изменения, происходящие в клетках сердца.

The aim of this study was to determine the possibility of studying the nature of the influence of cardiocytoprotectors on energy metabolism in cardiomyocytes using a model of human peripheral blood leukocytes.Materials and methods. Sixty Wistar rats were divided into groups: 1) intact rats; 2) rats with experimental myocardial ischemia; 3) rats with myocardial ischemia, which were injected with cardiocytoprotector – trimetazidine, 4) meldonium, 5) cytoflavin and 6) ethoxydol. Animals were taken out of the experiment 10 days after the administration of drugs by decapitation. The activities of pyruvate dehydrogenase and citrate synthase were determined in mitochondria of myocardial homogenates and in mitochondria of leukocytes by spectrophotometric methods.Results. The decrease in pyruvate dehydrogenase and citrate synthase activity in cardiomyocytes and in leukocytes were revealed in case of myocardial ischemia modeling. The introduction of cardiocytoprotectors led to the activation of these enzymes both in heart cells and in blood leukocytes. Direct positive correlations were obtained between the activity of pyruvate dehydrogenase in the mitochondria of cardiomyocytes and in the mitochondria of leukocytes (r = 0.811; p < 0.0001); between citrate synthase activity in the mitochondria of cardiomyocytes and in the mitochondria of leukocytes (r = 0.909; p < 0.0001).Conclusion. Changes in energy metabolism in blood leukocytes under the influence of cytoprotectors reflect similar changes occurring in heart cells.

лейкоциткардиомиоцитэнергетический обменцитопротекторыишемия миокардаleukocytecardiomyocyteenergy metabolismcytoprotectorsmyocardial ischemiaReferences2020 Clinical practice guidelines for stable coronary artery disease. Russian Journal of Cardiology. 2020; 25(11): 4076. (In Russ.). doi: 10.15829/1560-4071-2020-40762020 Clinical practice guidelines for stable coronary artery disease. Russian Journal of Cardiology. 2020; 25(11): 4076. (In Russ.). doi: 10.15829/1560-4071-2020-40762020 Clinical practice guidelines for chronic heart failure. Russian Journal of Cardiology. 2020; 25(11): 4083. (In Russ.). doi: 10.15829/1560-4071-2020-40832020 Clinical practice guidelines for chronic heart failure. Russian Journal of Cardiology. 2020; 25(11): 4083. (In Russ.). doi: 10.15829/1560-4071-2020-4083Umehara T, Oka H, Nakahara A, Matsuno H, Murakami H. Differential leukocyte count is associated with clinical phenotype in Parkinson’s disease. J Neurol Sci. 2020; 409: 116638. doi: 10.1016/j.jns.2019.116638Umehara T, Oka H, Nakahara A, Matsuno H, Murakami H. Differential leukocyte count is associated with clinical phenotype in Parkinson’s disease. J Neurol Sci. 2020; 409: 116638. doi: 10.1016/j.jns.2019.116638Vinodh Rajkumar R. Exercise Performance and Immune Competence [EPIC: Background of natural immunity, immune diversity and immuno-iatrogenesis. Int J Physiother Res. 2022; 10(3): 4250-4268. doi: 10.16965/ijpr.2022.124Vinodh Rajkumar R. Exercise Performance and Immune Competence [EPIC: Background of natural immunity, immune diversity and immuno-iatrogenesis. Int J Physiother Res. 2022; 10(3): 4250-4268. doi: 10.16965/ijpr.2022.124Schirrmacher V. Mitochondria at work: New insights into regulation and dysregulation of cellular energy supply and metabolism. Biomedicines. 2020; 8(11): 526. doi: 10.3390/biomedicines8110526Schirrmacher V. Mitochondria at work: New insights into regulation and dysregulation of cellular energy supply and metabolism. Biomedicines. 2020; 8(11): 526. doi: 10.3390/biomedicines8110526Zuurbier CJ, Bertrand L, Beauloye CR, Andreadou I, Ruiz‐Meana M, Jespersen NR, et al. Cardiac metabolism as a driver and therapeutic target of myocardial infarction. J Cell Mol Med. 2020; 24(11): 5937-5954. doi: 10.1111/jcmm.15180Zuurbier CJ, Bertrand L, Beauloye CR, Andreadou I, Ruiz‐Meana M, Jespersen NR, et al. Cardiac metabolism as a driver and therapeutic target of myocardial infarction. J Cell Mol Med. 2020; 24(11): 5937-5954. doi: 10.1111/jcmm.15180Dard L, Blanchard W, Huber C, Lacombe D, Rossignol R. Mitochondrial functions and rare diseases. Mol Aspects Med. 2020; 71: 100842. doi: 10.1016/j.mam.2019.100842Dard L, Blanchard W, Huber C, Lacombe D, Rossignol R. Mitochondrial functions and rare diseases. Mol Aspects Med. 2020; 71: 100842. doi: 10.1016/j.mam.2019.100842Sukhorukov VS. Individual peculiarities of tissue energy metabolism and their role in the development of childhood diseases. Russian Bulletin of Perinatology and Pediatrics. 2011; 56(2): 4-11. (In Russ.)Sukhorukov VS. Individual peculiarities of tissue energy metabolism and their role in the development of childhood diseases. Russian Bulletin of Perinatology and Pediatrics. 2011; 56(2): 4-11. (In Russ.)Huang Z, Xie N, Illes P, Di Virgilio F, Ulrich H, Semyanov A, et al. From purines to purinergic signalling: Molecular functions and human diseases. Signal Transduct Target Ther. 2021; 6(1): 162. doi: 10.1038/s41392-021-00553-zHuang Z, Xie N, Illes P, Di Virgilio F, Ulrich H, Semyanov A, et al. From purines to purinergic signalling: Molecular functions and human diseases. Signal Transduct Target Ther. 2021; 6(1): 162. doi: 10.1038/s41392-021-00553-zRomanov BK. Lysosome enzyme activity as a new diagnostic and prognostic criterium for the evaluation of cardiomyocyte damage rate. I.P. Pavlov Russian Medical Biological Herald. 2004; 1-2: 155-163. (In Russ.).Romanov BK. Lysosome enzyme activity as a new diagnostic and prognostic criterium for the evaluation of cardiomyocyte damage rate. I.P. Pavlov Russian Medical Biological Herald. 2004; 1-2: 155-163. (In Russ.).Dambrova M, Zuurbier CJ, Borutaite V, Liepinsh E, Makrecka-Kuka M. Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury. Free Radic Biol Med. 2021; 165: 24-37. doi: 10.1016/j.freeradbiomed. 2021.01.036Dambrova M, Zuurbier CJ, Borutaite V, Liepinsh E, Makrecka-Kuka M. Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury. Free Radic Biol Med. 2021; 165: 24-37. doi: 10.1016/j.freeradbiomed. 2021.01.036Vasyuk YuA, Kulikov KG, Kudryakov ON, Krikunova OV, Sadulaeva IA. Secondary mitochondrial dysfunction in acute coronary syndrome. Rational Pharmacotherapy in Cardiology. 2007; 3(1): 41-47. (In Russ.). doi: 10.20996/1819-6446-2007-3-1-41-47Vasyuk YuA, Kulikov KG, Kudryakov ON, Krikunova OV, Sadulaeva IA. Secondary mitochondrial dysfunction in acute coronary syndrome. Rational Pharmacotherapy in Cardiology. 2007; 3(1): 41-47. (In Russ.). doi: 10.20996/1819-6446-2007-3-1-41-47Vuononvirta J, Marelli-Berg FM, Poobalasingam T. Metabolic regulation of T lymphocyte motility and migration. Mol Aspects Med. 2021; 77: 100888. doi: 10.1016/j.mam.2020.100888Vuononvirta J, Marelli-Berg FM, Poobalasingam T. Metabolic regulation of T lymphocyte motility and migration. Mol Aspects Med. 2021; 77: 100888. doi: 10.1016/j.mam.2020.100888Hortová‐Kohoutková M, Lázničková P, Frič J. How immune‐cell fate and function are determined by metabolic pathway choice: The bioenergetics underlying the immune response. Bioessays. 2021; 43(2): 2000067. doi: 10.1002/bies.202000067Hortová‐Kohoutková M, Lázničková P, Frič J. How immune‐cell fate and function are determined by metabolic pathway choice: The bioenergetics underlying the immune response. Bioessays. 2021; 43(2): 2000067. doi: 10.1002/bies.202000067Koterov AN, Ushenkova LN, Zubenkova ES, Vaynson AA, Biryukov AP. Age relationships between major laboratory animals (mice, rats, hamsters and dogs) and humans: Relevance to age-related radiosensitivity and analysis of published data. Medical Radiology and Radiation Safety. 2018; 63(1): 5-27. (In Russ.). doi: 10.12737/article_5a82e4a3908213.56647014Koterov AN, Ushenkova LN, Zubenkova ES, Vaynson AA, Biryukov AP. Age relationships between major laboratory animals (mice, rats, hamsters and dogs) and humans: Relevance to age-related radiosensitivity and analysis of published data. Medical Radiology and Radiation Safety. 2018; 63(1): 5-27. (In Russ.). doi: 10.12737/article_5a82e4a3908213.56647014Rogozhina AA, Averkova AO, Zubova YeA, Minushkina LO, Brazhnik VA, Ivanova ON, et al. Incidence of familial hypercholesterolemia in patients with early manifestations of coronary artery disease: Data from a Russian multicenter study and metaanalysis. Russian Journal of Cardiology. 2023; 28(10): 5587. (In Russ.). doi: 10.15829/1560-4071-2023-5587Rogozhina AA, Averkova AO, Zubova YeA, Minushkina LO, Brazhnik VA, Ivanova ON, et al. Incidence of familial hypercholesterolemia in patients with early manifestations of coronary artery disease: Data from a Russian multicenter study and metaanalysis. Russian Journal of Cardiology. 2023; 28(10): 5587. (In Russ.). doi: 10.15829/1560-4071-2023-5587Putilina FYe. Method for determining citrate synthase activity. In: Methods of biochemical research (lipid and energy metabolism). Ed. by M.I. Prokhorova. Leningrad: Leningrad University Publ., 1982: 179-181. (In Russ.).Putilina FYe. Method for determining citrate synthase activity. In: Methods of biochemical research (lipid and energy metabolism). Ed. by M.I. Prokhorova. Leningrad: Leningrad University Publ., 1982: 179-181. (In Russ.).Yeshchenko ND. Method for determining pyruvate dehydrogenase activity. In: Methods of biochemical research (lipid and energy metabolism). Ed. by M.I. Prokhorova. Leningrad: Leningrad University Publ., 1982: 192-195. (In Russ.).Yeshchenko ND. Method for determining pyruvate dehydrogenase activity. In: Methods of biochemical research (lipid and energy metabolism). Ed. by M.I. Prokhorova. Leningrad: Leningrad University Publ., 1982: 192-195. (In Russ.).Prochownik EV, Wang H. The metabolic fates of pyruvate in normal and neoplastic cells. Cells. 2021; 10(4): 762. doi: 10.3390/cells10040762Prochownik EV, Wang H. The metabolic fates of pyruvate in normal and neoplastic cells. Cells. 2021; 10(4): 762. doi: 10.3390/cells10040762Maurer J, Hoene M, Weigert C. Signals from the circle: Tricarboxylic acid cycle intermediates as myometabokines. Metabolites. 2021; 11(8): 474. doi: 10.3390/metabo11080474Maurer J, Hoene M, Weigert C. Signals from the circle: Tricarboxylic acid cycle intermediates as myometabokines. Metabolites. 2021; 11(8): 474. doi: 10.3390/metabo11080474Roosterman D, Cottrell GS. Rethinking the citric acid cycle: Connecting pyruvate carboxylase and citrate synthase to the flow of energy and material. Int J Mol Sci. 2021; 22(2): 604. doi: 10.3390/ijms22020604Roosterman D, Cottrell GS. Rethinking the citric acid cycle: Connecting pyruvate carboxylase and citrate synthase to the flow of energy and material. Int J Mol Sci. 2021; 22(2): 604. doi: 10.3390/ijms22020604Guo Y, Pu WT. Cardiomyocyte maturation: New phase in development. Circ Res. 2020; 126(8): 1086-1106. doi: 10.1161/CIRCRESAHA.119.315862Guo Y, Pu WT. Cardiomyocyte maturation: New phase in development. Circ Res. 2020; 126(8): 1086-1106. doi: 10.1161/CIRCRESAHA.119.315862Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000; 86(5): 580-588. doi: 10.1161/01.res.86.5.580Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000; 86(5): 580-588. doi: 10.1161/01.res.86.5.580Bobescu E, Marceanu LG, Dima L, Balan A, Strempel CG, Covaciu A. Trimetazidine therapy in coronary artery disease: The impact on oxidative stress, inflammation, endothelial dysfunction, and long-term prognosis. Am J Ther. 2021; 28(5): e540-e547. doi: 10.1097/MJT.0000000000001430Bobescu E, Marceanu LG, Dima L, Balan A, Strempel CG, Covaciu A. Trimetazidine therapy in coronary artery disease: The impact on oxidative stress, inflammation, endothelial dysfunction, and long-term prognosis. Am J Ther. 2021; 28(5): e540-e547. doi: 10.1097/MJT.0000000000001430Romashchenko OV. Personalized trimetazidine prescription as a cytoprotective agent in patients with coronary artery disease. Russian Journal of Cardiology. 2021; 26(6): 106-114. (In Russ.). doi: 10.15829/1560-4071-2021-4532Romashchenko OV. Personalized trimetazidine prescription as a cytoprotective agent in patients with coronary artery disease. Russian Journal of Cardiology. 2021; 26(6): 106-114. (In Russ.). doi: 10.15829/1560-4071-2021-4532Larina VN. Multisystem effect of cytoprotection. Consilium Medicum. 2021; 23(1): 93-98. (In Russ.). doi: 10.26442/20751753.2021.1.200732Larina VN. Multisystem effect of cytoprotection. Consilium Medicum. 2021; 23(1): 93-98. (In Russ.). doi: 10.26442/20751753.2021.1.200732Berlato DG, de Bairros AV. Meldonium: Pharmacological, toxicological, and analytical aspects. Toxicology Research and Application. 2020; 4. doi: 10.1177/2397847320915143Berlato DG, de Bairros AV. Meldonium: Pharmacological, toxicological, and analytical aspects. Toxicology Research and Application. 2020; 4. doi: 10.1177/2397847320915143Nedogoda SV. Meldonium as a supernosological drug. Consilium Medicum. 2020; 22(5): 57-61. (In Russ.). doi: 10.26442/20751753.2020.5.200208Nedogoda SV. Meldonium as a supernosological drug. Consilium Medicum. 2020; 22(5): 57-61. (In Russ.). doi: 10.26442/20751753.2020.5.200208Shivakumar A, Yogendra Kumar MS. Critical review on the analytical mechanistic steps in the evaluation of antioxidant activity. Crit Rev Anal Chem. 2018; 48(3): 214-236. doi: 10.1080/10408347.2017.1400423Shivakumar A, Yogendra Kumar MS. Critical review on the analytical mechanistic steps in the evaluation of antioxidant activity. Crit Rev Anal Chem. 2018; 48(3): 214-236. doi: 10.1080/10408347.2017.1400423Zhigacheva VI, Krikunova IN, Binyukov IV, Mil E, Rusina I, Goloshchapov A. Etoxidol as a broad spectrum adaptogen. Curr Mol Pharmacol. 2023; 16(1): 109-115. doi: 10.2174/1874467215666220308115514Zhigacheva VI, Krikunova IN, Binyukov IV, Mil E, Rusina I, Goloshchapov A. Etoxidol as a broad spectrum adaptogen. Curr Mol Pharmacol. 2023; 16(1): 109-115. doi: 10.2174/1874467215666220308115514Romaschenko O, Pokrovsky M, Nadezhdin S, Rumbesht V, Zhernakova N, Alferov P, et al. Personalized approaches to the use of the antioxidant ethoxidol in patients with coronary heart disease. Journal of Nanostructures. 2022; 12(2): 343-352. doi: 10.22052/JNS.2022.02.011Romaschenko O, Pokrovsky M, Nadezhdin S, Rumbesht V, Zhernakova N, Alferov P, et al. Personalized approaches to the use of the antioxidant ethoxidol in patients with coronary heart disease. Journal of Nanostructures. 2022; 12(2): 343-352. doi: 10.22052/JNS.2022.02.011Novikov VE, Levchenkova OS, Ivantsova EN, Vorobieva VV. Mitochondrial dysfunctions and antihypoxants. Reviewers on Clinical Pharmacology and Drug Therapy. 2019; 17(4): 30-41. (In Russ.). doi: 10.7816/RCF17431-42Novikov VE, Levchenkova OS, Ivantsova EN, Vorobieva VV. Mitochondrial dysfunctions and antihypoxants. Reviewers on Clinical Pharmacology and Drug Therapy. 2019; 17(4): 30-41. (In Russ.). doi: 10.7816/RCF17431-42Romashchenko O.V. The influence of cytoflavin on the viability of blood leukocytes in patients with ischemic heart disease. Experimental and Clinical Pharmacology. 2021; 84(3): 17-21. (In Russ.). doi: 10.30906/0869-2092-2021-84-3-17-21Romashchenko O.V. The influence of cytoflavin on the viability of blood leukocytes in patients with ischemic heart disease. Experimental and Clinical Pharmacology. 2021; 84(3): 17-21. (In Russ.). doi: 10.30906/0869-2092-2021-84-3-17-21

The authors declare that there are no conflicts of interest present.