pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2020-8-2-100-111pmedpharm-687Research ArticleФАРМАКОЛОГИЯ И КЛИНИЧЕСКАЯ ФАРМАКОЛОГИЯPHARMACOLOGY AND CLINICAL PHARMACOLOGYИЗУЧЕНИЕ АНТИАТЕРОСКЛЕРОТИЧЕСКОЙ И ЭНДОТЕЛИОПРОТЕКТИВНОЙ АКТИВНОСТИ ПЕПТИДНЫХ АГОНИСТОВ ГЕТЕРОРЕЦЕПТОРА EPOR/CD131STUDY OF ANTIATHEROSCLEROTIC AND ENDOTHELIOPROTECTIVE ACTIVITY OF PEPTIDE AGONISTS OF EPOR/CD131 HETERORECEPTORhttps://orcid.org/0000-0002-7657-0937ПученковаОлеся А.PuchenkovaOlesya A.

6th year student of the Medical Institute

85, Pobeda Str., Belgorod, 30801

lesya759@yandex.ruhttps://orcid.org/0000-0002-6249-2464НадеждинСергей В.NadezhdinSergey V.

Candidate of Sciences (Biology), Researcher, the Research Institute of Pharmacology of Living Systems

85, Pobeda Str., Belgorod, 30801

sergey_nadezhdin@yahoo.comhttps://orcid.org/0000-0001-9706-0699СолдатовВладислав О.SoldatovVladislav O.

младший научный сотрудник

Junior Researcher, Center for Collective Use of IBG RAS

34/5, Vavilov Str., Moscow, 11933

zinkfingers@gmail.comЖученкоМаксим А.ZhuchenkoMaxim A.

Candidate of Sciences (Biology), the Head of the Sector

1, Academician Kurchatov Square, Moscow, 123098

maksim.zhuchenko@pharmapark.ruhttps://orcid.org/0000-0002-0259-7045КоршуноваДиана С.KorshunovaDiana S.

Junior Researcher

34/5, Vavilov Str., Moscow, 11933

korshunova@genebiology.ruhttps://orcid.org/0000-0002-8834-1111КубекинаМарина В.KubekinaMarina V.

аспирант, младший научный сотрудник Центра высокоточного редактирования и генетических технологий для биомедицины

postgraduate student, junior researcher at the Center for High-Precision Editing and Genetic Technologies for Biomedicine

34/5, Vavilov Str., Moscow, 11933

marykumy@gmail.comhttps://orcid.org/0000-0001-8170-4656КоршуновЕвгений Н.KorshunovEvgeny N.

The head of the vivarium, junior researcher

34/5, Vavilov Str., Moscow, 11933

korshunov@genebiology.ruhttps://orcid.org/0000-0001-5402-0697КорокинаЛилия В.KorokinaLiliya V.

Candidate of Sciences (Medicine), Assistant Professor, Researcher, the Research Institute of Pharmacology of Living Systems

85, Pobeda Str., Belgorod, 30801

korokina@mail.ruКуликовАлександр Л.GolubinskayaPolina A.

The Head of the Clinical Diagnostic Laboratory

22, Revolution of 1905 Str., Voronezh, 394030

alex-3031@yandex.ruhttps://orcid.org/0000-0002-1765-9042ГолубинскаяПолина А.KulikovAleksandr L.

заведующая клинико-диагностической лаборатории

Researcher, Research Institute of Pharmacology of Living Systems

85, Pobeda Str., Belgorod, 30801

polinapigeon@gmail.comhttps://orcid.org/0000-0003-3138-2075ПокровскийВладимир М.GureevVladimir V.

Doctor of Sciences (Medicine), Associate Professor, Professor of the Department of Pharmacology and Clinical Pharmacology

85, Pobeda Str., Belgorod, 30801

vmpokrovsky@yandex.ruhttps://orcid.org/0000-0002-8415-4562ПатрахановЕвгений А.PokrovskiyVladimir M.

5th year student of the Medical Institute

85, Pobeda Str., Belgorod, 30801

pateval7@gmail.comhttps://orcid.org/0000-0001-9102-3360ЛебедевПетр Р.PatrakhanovEvgeniy A.

5th year student of the Medical Institute

85, Pobeda Str., Belgorod, 30801

Artkeit@yandex.ruhttps://orcid.org/0000-0003-1433-1225ГуреевВладимир В.LebedevPetr R.

5th year student of the Medical Institute

85, Pobeda Str., Belgorod, 30801

produmen@yandex.ruhttps://orcid.org/0000-0003-0974-4818ДенисюкТатьяна А.DenisyukTatyana A.

Doctor of Sciences (Medicine), Associate Professor of the Department of Pharmacology

3, Karl Marx Str., Kursk, 305041

denitatyana@yandex.ruhttps://orcid.org/0000-0003-2941-0241БеляеваВероника С.BelyaevaVeronika S.

post-graduate student of the Department of Pharmacology and Clinical Pharmacology

85, Pobeda Str., Belgorod, 30801

nika.beliaeva@yandex.ruhttps://orcid.org/0000-0002-6244-2563МовчанЕвгения А.MovchanEvgeniya A.

postgraduate student of the Department of Pharmacology and Clinical Pharmacology

85, Pobeda Str., Belgorod, 30801

ms.movchan@mail.ruЛепетюхаЕлизавета И.LepetukhaElizaveta I.

postgraduate student of the Department of Pharmacology and Clinical Pharmacology

85, Pobeda Str., Belgorod, 30801

lisitsa007@bk.ruhttps://orcid.org/0000-0002-2761-6249ПокровскийМихаил В.PokrovskiyMikhail V.

Doctor of Sciences (Medicine), Professor of the Department of Pharmacology and Clinical Pharmacology, the Head of the Research Institute of Pharmacology of Living Systems

85, Pobeda Str., Belgorod, 30801

mpokrovsky@yandex.ruБелгородский государственный национальный исследовательский университетРоссияBelgorod State National Research UniversityRussian FederationБелгородский государственный национальный исследовательский университетРоссияFederal Publicly Funded Institution of Science “Institute of Gene Biology of the Russian Academy of Sciences”Russian FederationНИЦ «Курчатовский институт» - ГосНИИгенетикаРоссияRussian Research Center “Kurchatov Institute” – State Science Research Institute of GeneticsRussian FederationИнститут биологии гена РАНРоссияFederal Publicly Funded Institution of Science “Institute of Gene Biology of the Russian Academy of Sciences”Russian FederationФГБУН «Институт биологии гена РАН»РоссияFederal Publicly Funded Institution of Science “Institute of Gene Biology of the Russian Academy of Sciences”Russian FederationФГБУН «Института биологии гена РАН»РоссияFederal Publicly Funded Institution of Science “Institute of Gene Biology of the Russian Academy of Sciences”Russian FederationБелгородский государственный национальный исследовательский университетРоссияClinical diagnostic laboratory, Budgetary institution of public healthcare of the Voronezh Region “Voronezh Regional Clinical Ophthalmological Hospital”Russian FederationВоронежская областная клиническая офтальмологическая больницаРоссияBelgorod State National Research UniversityRussian FederationКурский государственный медицинский университетРоссияFederal State Budgetary Educational Institution of Higher Education “Kursk State Medical University”Russian Federation20201410202082100111Copyright © Пученкова О.А., Надеждин С.В., Солдатов В.О., Жученко М.А., Коршунова Д.С., Кубекина М.В., Коршунов Е.Н., Корокина Л.В., Куликов А.Л., Голубинская П.А., Покровский В.М., Патраханов Е.А., Лебедев П.Р., Гуреев В.В., Денисюк Т.А., Беляева В.С., Мовчан Е.А., Лепетюха Е.И., Покровский М.В., 20202020Пученкова О.А., Надеждин С.В., Солдатов В.О., Жученко М.А., Коршунова Д.С., Кубекина М.В., Коршунов Е.Н., Корокина Л.В., Куликов А.Л., Голубинская П.А., Покровский В.М., Патраханов Е.А., Лебедев П.Р., Гуреев В.В., Денисюк Т.А., Беляева В.С., Мовчан Е.А., Лепетюха Е.И., Покровский М.В.Puchenkova O.A., Nadezhdin S.V., Soldatov V.O., Zhuchenko M.A., Korshunova D.S., Kubekina M.V., Korshunov E.N., Korokina L.V., Golubinskaya P.A., Kulikov A.L., Gureev V.V., Pokrovskiy V.M., Patrakhanov E.A., Lebedev P.R., Denisyuk T.A., Belyaeva V.S., Movchan E.A., Lepetukha E.I., Pokrovskiy M.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/687Введение

Введение. Препараты, воздействующие на митохондриальную дисфункцию, оксидативный стресс, апоптоз и воспаление сосудистой стенки обладают высоким потенциалом при профилактике и лечении атеросклеротических поражений. В этой связи применение агонистов гетерорецептора EPOR/CD131, которые обладают подобным спектром фармакологических эффектов, является одной из перспективных стратегий в лечении кардиоваскулярных заболеваний.

Материалы и методы

Материалы и методы. Исследование было проведено на 68 самцах мышей C57Bl/6J. Атеросклероз моделировали на трансгенных животных с эндотелиоспецифичным нокдауном гена Polg путем моделирования балонной травмы и содержания на западной диете. Затем в течение 27и дней вводили изучаемые препараты 1 раз в 3 дня в дозе 20 мкг/кг. На 28й день животных эвтаназировали и оценивали площадь атеросклеротических бляшек. Также в тканях аорты определяли экспрессию генов, связанных с процессами воспаления, антиоксидантной защиты, апоптоза, ангиогенеза. Кроме того, было изучено эндотелиопротективное действие пептидов на первичных культурах эндотелиоцитов диких и трансгенных мышей Polg-D257A.

Результаты

Результаты. Мы не обнаружили статистичсеки значимого влияния препаратов на площадь липидной инфильтрации. Однако, исследуемые пептиды значимо уменьшили экспрессию провоспалительных генов iNos, Icam1, Vcam1, Sele, Il6, Tnfa, генов, связанных с ангиогенезом Vegfa, Flt-1 и Hif1a, экспрессию проапоптических факторов и более чем в 1,5 раза снизили соотношение Bax/Bcl-2. Кроме того, пептиды дозозависимо увеличили выживаемость эндотелиоцитов при добавлении H2O2 in vitro.

Заключение

Заключение. Используемые пептиды на основе эритропоэтина способны улучшать функциональное состояние сосудистой стенки на фоне атеросклеротичсекого поражения и оказывают угнетающее влияние на патобиологические процессы, связанные с митохондриальной дисфункцией. Кроме того, исследуемые пептиды оказывают значимый эндотелиопротективный эффект при индукции оксидативного стресса in vitro.

Introduction

Introduction. The drugs affecting a mitochondrial dysfunction, oxidative stresses, apoptosis and inflammation of the vascular wall, have a high potential for the prevention and treatment of atherosclerotic lesions. In this regard, the use of EPOR/CD131 heteroreceptor agonists which have a similar spectrum of pharmacological effects, is one of the promising strategies in the treatment of cardiovascular diseases.

Materials and Methods

Materials and Methods. The study was carried out on 68 C57Bl/6J male mice. Atherosclerosis was simulated in transgenic animals with an endotheliospecific knockdown of the Polg gene by simulating a balloon injury and keeping on a Western diet. Then, the studied drugs were injected once every 3 days at the dose of 20 μg/kg for 27 days. On the 28-th day, the animals were euthanized and the area of atherosclerotic plaques was assessed. The gene expression associated with the processes of inflammation, antioxidant protection, apoptosis, and angiogenesis was also determined in the aortic tissues. In addition, the endothelium protective effect of peptides on primary cultures of endothelial cells of wild and transgenic Polg-D257A mice was studied.

Results

Results. No statistically significant effect of drugs on the area of lipid infiltration have been found. However, the studied peptides have significantly reduced the expression of proinflammatory genes (iNos, Icam1, Vcam1, Sele, Il6, Tnfa), the genes associated with angiogenesis (Vegfa, Kdr, and Hif1a), the expression of proapoptic factors; they decreased the Bax/Bcl-2 ratio by more than 1.5 times. In addition, when supplemented with H2 O2  in vitro, peptides dose-dependently increased endothelial cell survival.

Conclusion

Conclusion. The erythropoietin-based peptides can be used to improve the functional state of the vascular wall against the background of atherosclerotic lesions and have a depressing effect on pathobiological processes associated with a mitochondrial dysfunction. In addition, the studied peptides have a significant endothelial protective effect in the induction of oxidative stress in vitro.

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