fcmedicineФундаментальная и клиническая медицинаFundamental and Clinical Medicine2500-07642542-0941КемГМУ10.23946/2500-0764-2023-8-4-85-100fcmedicine-791Research ArticleОБЗОРНЫЕ СТАТЬИREVIEW ARTICLESФакторы, индуцируемые гипоксией: детали создают «картину». Часть II. HIF-2Hypoxia-inducible factors: details create a picture. Part II. HIF-2https://orcid.org/0000-0003-3611-1186ИгнатенкоГ. А.IgnatenkoG. A.

Игнатенко Григорий Анатольевич - доктор медицинских наук, профессор, заведующий кафедрой пропедевтики внутренних болезней.

283003, Донецкая Народная Республика, Донецк, пр. Ильича, д. 16

Grigoriy A. Ignatenko - MD, DSc, Professor, Head of the Department of internal diseases propaedeutics, M. Gorky Donetsk State Medical University.

16, Ilyich Avenue, Donetsk, Donetsk People's Republic, 283003

rektor@dnmu.ruhttps://orcid.org/0000-0001-7452-7006БондаренкоН. Н.BondarenkoN. N.

Бондаренко Надежда Николаевна - доктор медицинских наук, профессор, заведующая кафедрой физиологии с лабораторией теоретической и прикладной нейрофизиологии им. акад. В.Н. Казакова.

283003, Донецкая Народная Республика, Донецк, пр. Ильича, д. 16

Nadezhda N. Bondarenko - MD, DSc, Professor, Head of the Academician V.N. Kazakov Department of Physiology with the Laboratory of Theoretical and Applied Neurophysiology, M. Gorky Donetsk State Medical University.

16, Ilyich Avenue, Donetsk, Donetsk People's Republic, 283003

https://orcid.org/0000-0002-7999-8656ДубоваяА. В.DubovayaA. V.

Дубовая Анна Валериевна - доктор медицинских наук, профессор, заведующая кафедрой педиатрии №3.

283003, Донецкая Народная Республика, Донецк, пр. Ильича, д. 16

Anna V. Dubovaya - MD, DSc, Professor, Head of the Department of Pediatrics №3, M. Gorky Donetsk State Medical University.

16, Ilyich avenue, Donetsk, Donetsk People's Republic, 283003

https://orcid.org/0009-0001-2138-2277ИгнатенкоТ. С.IgnatenkoT. S.

Игнатенко Татьяна Степановна - доктор медицинских наук профессор кафедры пропедевтики внутренних болезней.

283003, Донецкая Народная Республика, Донецк, пр. Ильича, д. 16

Tatyana S. Ignatenko - MD, DSc, Professor of the Department of internal diseases propaedeutics, M. Gorky Donetsk State Medical University.

16, Ilyich Avenue, Donetsk, Donetsk People's Republic, 283003

https://orcid.org/0009-0009-4364-1995ВалигунЯ. С.ValigunYa. S.

Валигун Янина Сергеевна - ассистент кафедры трансплантологии и клинической лабораторной диагностики.

283003, Донецкая Народная Республика, Донецк, пр. Ильича, д. 16

Yanina S. Valigun - Assistant of the Professor, Department of transplantology and clinical laboratory diagnostics M. Gorky Donetsk State Medical University.

16, Ilyich Avenue, Donetsk, Donetsk People's Republic, 283003

https://orcid.org/0000-0002-7454-6685БеляеваЕ. А.BelyaevaE. A.

Беляева Елена Александровна - кандидат химических наук, доцент кафедры фармацевтической и медицинской химии.

283003, Донецкая Народная Республика, Донецк, пр. Ильича, д. 16

Elena А. Belyaeva - PhD (Chemistry), Associate Professor of the Department of Pharmaceutical and Medical Chemistry, M. Gorky Donetsk State Medical University.

16, Ilyich avenue, Donetsk, Donetsk People's Republic, 283003

https://orcid.org/0009-0006-5316-9813ГаврилякВ. Г.GavrilyakV. G.

Гавриляк Валентина Геннадьевна - кандидат медицинских наук, главный врач ГБУ «Больница интенсивного лечения г. Мариуполя», координатор учреждений здравоохранения г. Мариуполя.

Донецкая Народная Республика, Мариуполь, ул. 50 лет СССР, 46

Valentina G. Gavrilyak - MD, PhD, Chief physician of the “Intensive Treatment Hospital of Mariupol”, coordinator of healthcare institutions of Mariupol.

46, 50 Let USSR St., Mariupol, Donetsk People's Republic

ФГБОУ ВО «Донецкий государственный медицинский университет имени М. Горького» Министерства здравоохранения Российской ФедерацииРоссияM. Gorky Donetsk State Medical UniversityRussian Federation2023020120248485100Copyright © Игнатенко Г.А., Бондаренко Н.Н., Дубовая А.В., Игнатенко Т.С., Валигун Я.С., Беляева Е.А., Гавриляк В.Г., 20242024Игнатенко Г.А., Бондаренко Н.Н., Дубовая А.В., Игнатенко Т.С., Валигун Я.С., Беляева Е.А., Гавриляк В.Г.Ignatenko G.A., Bondarenko N.N., Dubovaya A.V., Ignatenko T.S., Valigun Y.S., Belyaeva E.A., Gavrilyak 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://fcm.kemsmu.ru/jour/article/view/791

В настоящем обзоре представлены современные сведения о роли фактора, индуцируемого гипоксией-2 (HIF-2) в условиях физиологической тканевой гипоксии и при патологических гипоксических состояниях. Описаны структурно-функциональные особенности субъединиц HIF-2 (HIF-2α и HIF-β), способы их регуляции в условиях нормоксии и гипоксии. Спектр клеток, экспрессирующих HIF-2α, достаточно разнообразен: эндотелиальные клетки кровеносных сосудов, фибробласты почек, гепатоциты, интерстициальные клетки (телоциты) поджелудочной железы, эпителиальные клетки, выстилающие слизистую оболочку кишечника, альвеолоциты II типа, глиальные клетки, производные клеток нервного гребня (хромаффиноциты надпочечника). HIF-2α-зависимые транскрипционные эффекты высоко локус-специфичны и проявляются лишь при определенных обстоятельствах. Регуляция трансляции HIF-2α может осуществляться двумя классами регуляторных молекул (РНК-связывающие белки и мРНК) путем изменения скорости трансляции вследствие связывания с 3'- или 5'-нетранслируемой областью мРНК (3'-или 5'-UTR) конкретных мишеней. Активность HIF-2α регулируется преимущественно на посттрансляционном уровне с помощью различных сигнальных механизмов, реализуемых на уровне экспрессии мРНК, трансляции мРНК, стабильности белка и транскрипционной активности. При нормоксии каноническая регуляция активности HIF-2α определяется кислородзависимыми механизмами, а в условиях гипоксии - неканоническими (кислороднезависимыми), путем фосфорилирования, сумоилирования, ацетилирования, метилирования и др., вызывая позитивные и негативные эффекты. Установлено, что HIF влияет на сигнальные пути, влияющие на эмбриональное развитие, метаболизм, воспаление и физиологию функциональных систем, а также работает в долгосрочных ответах на хроническую гипоксию, в течение которой регулирует ангиогенез, метаболизм глюкозы, железа, липидов, клеточный цикл, метастазирование и другие процессы. Изучение изменений внутриклеточного содержания HIF-2α и транскрипционной активности HIF-2 позволит разрабатывать эффективные способы коррекции различных заболеваний, сопровождающихся системной и локальной кислородной недостаточностью.

This review presents current information on the role of hypoxia-inducible factor-2 (HIF-2) under conditions of physiological tissue hypoxia and pathological hypoxic conditions. The structural and functional features of HIF-2 subunits (HIF-2α and HIF-β) and methods of their regulation under conditions of normoxia and hypoxia are described. The spectrum of cells expressing HIF-2α is quite diverse: endothelial cells of blood vessels, kidney fibroblasts, hepatocytes, interstitial cells (telocytes) of the pancreas, epithelial cells lining the intestinal mucosa, type II alveolocytes, glial cells, derivatives of neural crest cells (chromaffinocytes of the adrenal gland). HIF-2α -dependent transcriptional effects are highly locus specific and occur only under certain circumstances. Regulation of HIF-2α translation can be accomplished by two classes of regulatory molecules (RNA-binding proteins and mR-NAs) by altering the rate of translation due to binding to the 3' or 5' untranslated region of mRNA (3' or 5' UTR) of specific targets. HIF-2α activity is regulated primarily at the post-translational level by various signaling mechanisms at the level of mRNA expression, mRNA translation, protein stability, and transcriptional activity. Under normoxia, the canonical regulation of HIF-2α activity is determined by oxygen-dependent mechanisms, and under hypoxia conditions - by non-canonical (oxygen-independent) mechanisms, through phosphorylation, SUMOlyated, acetylation, methylation, etc., causing positive and negative effects. It has been established that HIF influences signaling pathways affecting embryonic development, metabolism, inflammation and the physiology of functional systems, and also works in long-term responses to chronic hypoxia, during which it regulates angiogenesis, glucose, iron, lipid metabolism, cell cycle, metastasis and other processes. Studying changes in the intracellular content of HIF-2α and the transcriptional activity of HIF-2 will allow us to develop effective methods for correcting various diseases accompanied by systemic and local oxygen deficiency.

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