anatomyЖурнал анатомии и гистопатологииJournal of Anatomy and Histopathology2225-7357N.N. Burdenko Voronezh State Medical University10.18499/2225-7357-2024-13-2-54-62anatomy-1941Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL PAPERSОценка влияния окситоцина на структурно-функциональные изменения миокарда при экспериментальной сердечной недостаточностиEvaluation of the effect of oxytocin on structural and functional changes of the myocardium in experimental heart failurehttps://orcid.org/0000-0002-7892-1841СтарченкоА. Д.StarchenkoA. D.

Старченко Анастасия Дмитриевна – ассистент кафедры внутренних болезней

ул. Советская, 6, Оренбург, 460014

Anastasiya D. Starchenko – assistant of the Department of Internal diseases

ul. Sovetskaya, 6, Orenburg, 460014

doctornastenka@mail.ruhttps://orcid.org/0000-0001-6271-8841ЛисковаЮ. В.LiskovaYu. V.

Лискова Юлия Владимировна – д-р. мед. наук, доцент, профессор кафедры факультетской терапии лечебного факультета

Москва

Yuliya V. Liskova – Doct. Sci. (Med.), associate professor, professor of the Department of Faculty therapy of Faculty of General Medicine

Moscow

liskovaj@bk.ruhttps://orcid.org/0000-0002-6107-0534СтадниковА. А.StadnikovA. A.

Стадников Александр Абрамович – д-р. биол. наук, профессор, зав. кафедрой гистологии, цитологии и эмбриологии

Оренбург

Aleksandr A. Stadnikov – Doct. Sci. (Biol.), professor, head of the Department of histology, cytology and embryology

Orenburg

stadnikov@yandex.ruhttps://orcid.org/0009-0002-7050-8320МясниковаА. А.MyasnikovaA. A.

Мясникова Анастасия Алексеевна – студентка

Оренбург

Anastasiya A. Myasnikova – student

Orenburg

anastasia350@bk.ruОренбургский государственный медицинский университетOrenburg State Medical UniversityРоссийский национальный исследовательский медицинский университет им. Н.И. ПироговаN.I. Pirogov Russian National Research Medical University2024040720241325462Copyright © Старченко А.Д., Лискова Ю.В., Стадников А.А., Мясникова А.А., 20242024Старченко А.Д., Лискова Ю.В., Стадников А.А., Мясникова А.А.Starchenko A.D., Liskova Y.V., Stadnikov A.A., Myasnikova A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://anatomy.elpub.ru/jour/article/view/1941

Цель исследования – изучить влияние окситоцина на структурно-функциональную реорганизацию миокарда при экспериментальной сердечной недостаточности (ЭСН) Материал и методы. Сердечную недостаточность моделировали на половозрелых крысах обоего пола линии Wistar (n=36). С 7-го дня эксперимента части животным с ЭСН вводили окситоцин в дозе 0,5 Ед/кг массы тела ежедневно внутримышечно в течение недели. Полученный материал (сердце, миокард левого желудочка (ЛЖ)) был изучен методами световой микроскопии, морфометрии и иммуногистохимии с оценкой экспрессии белков caspase-3, bcl-2, ki-67. Результаты. Комплексный анализ гистологических препаратов показал, что при сердечной недостаточности патологические изменения происходят во всех структурах миокарда ЛЖ (в кардиомиоцитах (КМЦ), сосудах микроциркуляторного русла, соединительнотканной строме). На фоне введения окситоцина наблюдается увеличение объемной плотности (ОП) сердечных миоцитов, капилляров и уменьшение ОП компонентов стромы. Установлено ингибирование окситоцином проапоптотической доминанты и активация репаративных процессов в миокарде. Отмечались уменьшение количества caspase-3-позитивных сердечных миоцитов и увеличение КМЦ, экспрессирующих bcl-2 и ki-67, у животных обоего пола с ЭСН. При воздействии окситоцина выявлена более значимая активация регенераторного и антиапоптотического потенциала в группе самок с ЭСН. Заключение. Результаты исследования демонстрируют наличие кардиопротективного действия окситоцина на структуры миокарда при сердечной недостаточности, характеризующиеся стимуляцией васкулогенеза, ингибированием процессов фиброза и апоптоза, а также активацией путей клеточного адаптивного ремоделирования миокарда. Выявлены половые особенности влияния окситоцина на миокард, что дает новое представление о роли окситоцинергической системы в сердце.

The aim of the study was to evaluate the effect of oxytocin on the structural and functional reorganization of the myocardium in experimental heart failure (EHF) Material and methods. Heart failure was modeled on mature rats of both sexes of the Wistar line (n=36). From the 7th day of the experiment, oxytocin was administered to animals with EHF at a dose of 0.5 U / kg of body weight daily intramuscularly for a week. The obtained material (heart, left ventricular (LV) myocardium) was studied by light microscopy, morphometry, and immunohistochemistry (expression of caspase-3, bcl-2, ki-67 proteins). Results. A comprehensive analysis of histological preparations showed that in heart failure, pathological changes occur in all structures of the LV myocardium (in cardiomyocytes (CMC), vessels of the microvasculature, connective tissue stroma). Against the background of the introduction of oxytocin, there is an increase in the volume density (VD) of cardiac myocytes, capillaries and a decrease in the VD of stromal components. Oxytocin inhibition of the proapoptotic dominant and activation of reparative processes in the myocardium were established: there was a decrease in the number of caspase-3-positive cardiac myocytes and an increase in CMC expressing bcl-2 and ki-67 in animals of both sexes with EHF. Under the influence of oxytocin, a more significant activation of regenerative and antiapoptotic potential was revealed in the group of females with EHF. Conclusion. The totality of the data obtained as a result of the study indicates the cardioprotective effect of oxytocin on myocardial structures in heart failure, characterized by stimulation of vasculogenesis, inhibition of fibrosis and apoptosis, and activation of cellular adaptive myocardial remodeling pathways. The biological effect of oxytocin on the myocardium is characterized by gender-specific features of the realization of its effects, which gives a new understanding of the role of the oxytocinergic system in the heart.

окситоцинремоделирование миокардаэкспериментальная сердечная недостаточностьапоптозкардиопротекцияoxytocinmyocardial remodelingexperimental heart failureapoptosiscardioprotectionИсследование выполнено при финансовой поддержке университетского гранта №ГР/2021/230/2/11 от 11.05.2021 года на базе ФГБОУ ВО ОрГМУ Минздрава РоссииThe study was carried out with the financial support of university grant No. GR/2021/230/2/11 dated May 11, 2021 on the basis of Orenburg State Medical UniversityReferencesИммуногистохимические методы: Руководство. Пер. с англ. под ред. Г.А.Франка и П.Г.Малькова. М., 2011.Immunogistokhimicheskie metody: Rukovodstvo. Per. s angl. pod red. GA Franka i PG Mal'kova. Moscow, 2011 (in Russ.).Лискова Ю.В., Саликова С.П., Стадников А.А. Структурная реорганизация миокарда овариэктомированных крыс с экспериментальной сердечной недостаточностью при введении мелатонина. Морфология. 2013;5(144):25–9.Liskova YuV, Salikova SP, Stadnikov AA. Structural Reorganization of the Myocardium in Ovariectomized Rats with Experimental Heart Failure after Melatonin Administration. Morphology. 2013;5(144):25–9 (in Russ.).Лискова Ю.В., Саликова С.П., Стадников А.А. Экспериментальные модели сердечной недостаточности: состояние вопроса и результаты собственного исследования. Морфологические ведомости. 2014;1(22):46–53.Liskova YuV, Salikova SP, Stadnikov AA. Experimental Models a Heart Failure: Condition of a Question and Results Own Research. Morphological Newsletter. 2014;1(22):46–53 (in Russ.).Ноздрин В.И., Барашкова С.А., Семечко В.В., Артемьев В.Н. Гистологическая техника: учебное пособие. 3-е изд., доп. и перераб. Омск – Орел: Омская областная типография. 2006.Nozdrin VI, Barashkova SA, Semechko VV, Artemyev VN. Histologicheskaya technika: uchebnoe posobie. 3rd ed., supplement and revision. Omsk – Orel: Omsk Regional Printing House. 2006 (in Russ.).Обрезан А.Г., Куликов Н.В. Нейрогуморальный дисбаланс при хронической сердечной недостаточности: классические и современные позиции. Российский кардиологический журнал. 2017;9(149):83–92. dоi: 10.15829/1560-4071-2017-9-83-92Obrezan AG, Kulikov NV. Neuro-humoral Disbalance in Chronic Heart Failure: Classic and Modern Perspectives. Russian journal of cardiology. 2017;9(149):83–92 (in Russ.). dоi: 10.15829/1560-4071-2017-9-83-92Bacova BS, Andelova K, Sykora M, Egan Benova T, Barancik M, Kurahara LH, et al. Does Myocardial Atrophy Represent Anti-Arrhythmic Phenotype? Biomedicines. 2022 Nov 4;10(11):2819–9. doi: 10.3390/biomedicines10112819Bacova BS, Andelova K, Sykora M, Egan Benova T, Barancik M, Kurahara LH, et al. Does Myocardial Atrophy Represent Anti-Arrhythmic Phenotype? Biomedicines. 2022 Nov 4;10(11):2819–9. doi: 10.3390/biomedicines10112819Buemann B, Uvnäs-Moberg K. Oxytocin may have a therapeutical potential against cardiovascular disease. Possible pharmaceutical and behavioral approaches. Medical Hypotheses. 2020 May;138:1095–7. doi: 10.1016/j.mehy.2020.109597Buemann B, Uvnäs-Moberg K. Oxytocin may have a therapeutical potential against cardiovascular disease. Possible pharmaceutical and behavioral approaches. Medical Hypotheses. 2020 May;138:1095–7. doi: 10.1016/j.mehy.2020.109597Carter HE, Schofield D, Shrestha R. Productivity costs of cardiovascular disease mortality across disease types and socioeconomic groups. Open Heart. 2019 Feb;6(1):e000939. doi: 10.1136/openhrt-2018-000939Carter HE, Schofield D, Shrestha R. Productivity costs of cardiovascular disease mortality across disease types and socioeconomic groups. Open Heart. 2019 Feb;6(1):e000939. doi: 10.1136/openhrt-2018-000939Chatterjee NA, Singh JP. Autonomic modulation and cardiac arrhythmias: old insights and novel strategies. EP Europace. 2021 May 29;23(11):1708–21. doi: 10.1093/europace/euab118Chatterjee NA, Singh JP. Autonomic modulation and cardiac arrhythmias: old insights and novel strategies. EP Europace. 2021 May 29;23(11):1708–21. doi: 10.1093/europace/euab118Corsetti G, Chen-Scarabelli C, Romano C, Pasini E, Dioguardi FS, Onorati F, et al. Autophagy and Oncosis/Necroptosis Are Enhanced in Cardiomyocytes from Heart Failure Patients. Medical Science Monitor Basic Research. 2019 Feb 4;25:33–44. doi: 10.12659/MSMBR.913436Corsetti G, Chen-Scarabelli C, Romano C, Pasini E, Dioguardi FS, Onorati F, et al. Autophagy and Oncosis/Necroptosis Are Enhanced in Cardiomyocytes from Heart Failure Patients. Medical Science Monitor Basic Research. 2019 Feb 4;25:33–44. doi: 10.12659/MSMBR.913436Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease. Physiological Reviews. 2019 Oct 1;99(4):1765–817. doi: 10.1152/physrev.00022.2018Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN. Fundamental Mechanisms of Regulated Cell Death and Implications for Heart Disease. Physiological Reviews. 2019 Oct 1;99(4):1765–817. doi: 10.1152/physrev.00022.2018Dyavanapalli J, Rodriguez J, Rocha dos Santos C, Escobar JB, Dwyer MK, Schloen J, et al. Activation of Oxytocin Neurons Improves Cardiac Function in a Pressure-Overload Model of Heart Failure. JACC: Basic to Translational Science. 2020 May;5(5):484–97. doi: 10.1016/j.jacbts.2020.03.007Dyavanapalli J, Rodriguez J, Rocha dos Santos C, Escobar JB, Dwyer MK, Schloen J, et al. Activation of Oxytocin Neurons Improves Cardiac Function in a Pressure-Overload Model of Heart Failure. JACC: Basic to Translational Science. 2020 May;5(5):484–97. doi: 10.1016/j.jacbts.2020.03.007Ferrario CM. Cardiac remodelling and RAS inhibition. Therapeutic Advances in Cardiovascular Disease. 2016 Apr 21;10(3):162–71. doi: 10.1177/1753944716642677Ferrario CM. Cardiac remodelling and RAS inhibition. Therapeutic Advances in Cardiovascular Disease. 2016 Apr 21;10(3):162–71. doi: 10.1177/1753944716642677Garrott K, Dyavanapalli J, Cauley E, Dwyer MK, Kuzmiak-Glancy S, Wang X, et al. Chronic activation of hypothalamic oxytocin neurons improves cardiac function during left ventricular hypertrophy-induced heart failure. Cardiovascular research. 2017 May 2;113(11):1318–28. doi: 10.1093/cvr/cvx084Garrott K, Dyavanapalli J, Cauley E, Dwyer MK, Kuzmiak-Glancy S, Wang X, et al. Chronic activation of hypothalamic oxytocin neurons improves cardiac function during left ventricular hypertrophy-induced heart failure. Cardiovascular research. 2017 May 2;113(11):1318–28. doi: 10.1093/cvr/cvx084Gong R, Jiang Z, Zagidullin N, Liu T, Cai B. Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration. Signal Transduction and Targeted Therapy. 2021 Jan 27;6(1):31. doi: 10.1038/s41392-020-00413-2Gong R, Jiang Z, Zagidullin N, Liu T, Cai B. Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration. Signal Transduction and Targeted Therapy. 2021 Jan 27;6(1):31. doi: 10.1038/s41392-020-00413-2Gruber C, Nink N, Nikam S, Magdowski G, Kripp G, Voswinckel R, et al. Myocardial remodelling in left ventricular atrophy induced by caloric restriction. Journal of Anatomy. 2011 Nov 13;220(2):179–85. doi: 10.1111/j.1469-7580.2011.01453.xGruber C, Nink N, Nikam S, Magdowski G, Kripp G, Voswinckel R, et al. Myocardial remodelling in left ventricular atrophy induced by caloric restriction. Journal of Anatomy. 2011 Nov 13;220(2):179–85. doi: 10.1111/j.1469-7580.2011.01453.xHeckle MR, Flatt DM, Sun Y, Mancarella S, Marion TN, Gerling IC, et al. Atrophied cardiomyocytes and their potential for rescue and recovery of ventricular function. Heart failure reviews. 2016 Feb 12;21(2):191–8. doi: 10.1007/s10741-016-9535-xHeckle MR, Flatt DM, Sun Y, Mancarella S, Marion TN, Gerling IC, et al. Atrophied cardiomyocytes and their potential for rescue and recovery of ventricular function. Heart failure reviews. 2016 Feb 12;21(2):191–8. doi: 10.1007/s10741-016-9535-xJankowski M, Wang D, Danalache B, Gangal M, Gutkowska J. Cardiac oxytocin receptor blockade stimulates adverse cardiac remodeling in ovariectomized spontaneously hypertensive rats. American Journal of Physiology-Heart and Circulatory Physiology. 2010 Aug;299(2):H265–74. doi: 10.1152/ajpheart.00487.2009Jankowski M, Wang D, Danalache B, Gangal M, Gutkowska J. Cardiac oxytocin receptor blockade stimulates adverse cardiac remodeling in ovariectomized spontaneously hypertensive rats. American Journal of Physiology-Heart and Circulatory Physiology. 2010 Aug;299(2):H265–74. doi: 10.1152/ajpheart.00487.2009Liu H, Xie Q, Xin BM, Liu JL, Liu Y, Li YZ, et al. Inhibition of autophagy recovers cardiac dysfunction and atrophy in response to tail-suspension. Life Sciences. 2015 Jan 15;121:1–9. doi: 10.1016/j.lfs.2014.10.023Liu H, Xie Q, Xin BM, Liu JL, Liu Y, Li YZ, et al. Inhibition of autophagy recovers cardiac dysfunction and atrophy in response to tail-suspension. Life Sciences. 2015 Jan 15;121:1–9. doi: 10.1016/j.lfs.2014.10.023Meng F, Xie B, Martin JF. Targeting the Hippo pathway in heart repair. Cardiovascular Research. 2021 Sep 16;118(11):2402–14. doi: 10.1093/cvr/cvab291Meng F, Xie B, Martin JF. Targeting the Hippo pathway in heart repair. Cardiovascular Research. 2021 Sep 16;118(11):2402–14. doi: 10.1093/cvr/cvab291Penna C, Granata R, Tocchetti C, Gallo M, Alloatti G, Pagliaro P. Endogenous Cardioprotective Agents: Role in Pre and Postconditioning. Current drug targets. 2015 Aug 12;16(8):843–67. doi: 10.2174/1389450116666150309115536Penna C, Granata R, Tocchetti C, Gallo M, Alloatti G, Pagliaro P. Endogenous Cardioprotective Agents: Role in Pre and Postconditioning. Current drug targets. 2015 Aug 12;16(8):843–67. doi: 10.2174/1389450116666150309115536Pyner S. The heart is lost without the hypothalamus. Handbook of clinical neurology. 2021 Jan 1;(182):355–67. doi: 10.1016/B978-0-12-819973-2.00024-1Pyner S. The heart is lost without the hypothalamus. Handbook of clinical neurology. 2021 Jan 1;(182):355–67. doi: 10.1016/B978-0-12-819973-2.00024-1Ross JA, Stroud MJ. The Nucleus: Mechanosensing in cardiac disease. The International Journal of Biochemistry & Cell Biology. 2021 Aug;137:106035. doi: 10.1016/j.biocel.2021.106035Ross JA, Stroud MJ. The Nucleus: Mechanosensing in cardiac disease. The International Journal of Biochemistry & Cell Biology. 2021 Aug;137:106035. doi: 10.1016/j.biocel.2021.106035Schirone L, Forte M, Palmerio S, Yee D, Nocella C, Angelini F, et al. A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling. Oxidative Medicine and Cellular Longevity. 2017;2017:1–16. doi: 10.1155/2017/3920195Schirone L, Forte M, Palmerio S, Yee D, Nocella C, Angelini F, et al. A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling. Oxidative Medicine and Cellular Longevity. 2017;2017:1–16. doi: 10.1155/2017/3920195Sudi S, Tanaka T, Oda S, Nishiyama K, Nishimura A, Sunggip C, et al. TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy. Scientific Reports. 2019 Jul 5;9(1):9785–5. doi: 10.1038/s41598-019-46252-2Sudi S, Tanaka T, Oda S, Nishiyama K, Nishimura A, Sunggip C, et al. TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy. Scientific Reports. 2019 Jul 5;9(1):9785–5. doi: 10.1038/s41598-019-46252-2Yap J, Chia SY, Lim FY, Allen JC, Teo L, Sim D, et al. The Singapore Heart Failure Risk Score: Prediction of Survival in Southeast Asian Patients. Annals, Academy of Medicine, Singapore/Annals of the Academy of Medicine, Singapore. 2019 Mar 15;48(3):86–94. doi: 10.47102/annals-acadmedsg.v48n3p86Yap J, Chia SY, Lim FY, Allen JC, Teo L, Sim D, et al. The Singapore Heart Failure Risk Score: Prediction of Survival in Southeast Asian Patients. Annals, Academy of Medicine, Singapore/Annals of the Academy of Medicine, Singapore. 2019 Mar 15;48(3):86–94. doi: 10.47102/annals-acadmedsg.v48n3p86Ytrehus K, Hulot JS, Perrino C, Schiattarella GG, Madonna R. Perivascular fibrosis and the microvasculature of the heart. Still hidden secrets of pathophysiology? Vascular Pharmacology. 2018 Aug;107:78–83. doi: 10.1016/j.vph.2018.04.007Ytrehus K, Hulot JS, Perrino C, Schiattarella GG, Madonna R. Perivascular fibrosis and the microvasculature of the heart. Still hidden secrets of pathophysiology? Vascular Pharmacology. 2018 Aug;107:78–83. doi: 10.1016/j.vph.2018.04.007Wasserman AH, Huang AR, Lewis-Israeli YR, Dooley MD, Mitchell AL, Venkatesan M, et al. Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury. Frontiers in Cell and Developmental Biology. 2022 Sep 30;10:985298. doi: 10.3389/fcell.2022.985298Wasserman AH, Huang AR, Lewis-Israeli YR, Dooley MD, Mitchell AL, Venkatesan M, et al. Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury. Frontiers in Cell and Developmental Biology. 2022 Sep 30;10:985298. doi: 10.3389/fcell.2022.985298Wsol A, Kasarello K, Kuch M, Gala K, Cudnoch-Jedrzejewska A. Increased Activity of the Intracardiac Oxytocinergic System in the Development of Postinfarction Heart Failure. BioMed research international. 2016 Jan 1;2016:1–7. doi: 10.1155/2016/3652068Wsol A, Kasarello K, Kuch M, Gala K, Cudnoch-Jedrzejewska A. Increased Activity of the Intracardiac Oxytocinergic System in the Development of Postinfarction Heart Failure. BioMed research international. 2016 Jan 1;2016:1–7. doi: 10.1155/2016/3652068

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