kpcczКомплексные проблемы сердечно-сосудистых заболеванийComplex Issues of Cardiovascular Diseases2306-12782587-9537Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”10.17802/2306-1278-2024-13-3S-191-207kpccz-1526Research ArticleАНАЛИТИЧЕСКИЙ ОБЗОР. Патологическая физиологияREVIEWS. Pathological physiologyСОВРЕМЕННЫЕ ПОДХОДЫ К ИДЕНТИФИКАЦИИ КЛЕТОЧНЫХ МАРКЕРОВ ДИСФУНКЦИИ ЭНДОТЕЛИЯCURRENT APPROACHES TO THE IDENTIFICATION OF CELLULAR MARKERS OF ENDOTHELIAL DYSFUNCTIONhttps://orcid.org/0000-0003-4124-2316БогдановЛев АлександровичBogdanovLeo A.

кандидат биологических наук научный сотрудник лаборатории молекулярной, трансляционной и цифровой медицины отдела экспериментальной медицины федерального государственного бюджетного научного учреждения «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Российская Федерация

PhD, Researcher, Laboratory for Molecular, Translational, and Digital Medicine, Department of Experimental Medicine, Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russian Federation

bogdanovleone@gmail.comhttps://orcid.org/0000-0001-6840-1116КошелевВладислав АлександровичKoshelevVladislav A.

младший научный сотрудник лаборатории молекулярной, трансляционной и цифровой медицины отдела экспериментальной медицины федерального государственного бюджетного научного учреждения «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Российская Федерация

Junior Researcher, Laboratory for Molecular, Translational, and Digital Medicine, Department of Experimental Medicine, Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russian Federation

vladkoshelev80@gmail.comhttps://orcid.org/0000-0002-5558-3229МухамадияровРинат АвхадиевичMukhamadiyarovRinat A.

кандидат биологических наук старший научный сотрудник лаборатории молекулярной, трансляционной и цифровой медицины федерального государственного бюджетного научного учреждения «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Российская Федерация

PhD, Senior Researcher, Laboratory for Molecular, Translational, and Digital Medicine, Department of Experimental Medicine, Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russian Federation

rem2257@gmail.comhttps://orcid.org/0000-0003-2810-3100КаноныкинаАнастасия ЮрьевнаKanonykinaAnastasia Yu.

младший научный сотрудник лаборатории молекулярной, трансляционной и цифровой медицины отдела экспериментальной медицины федерального государственного бюджетного научного учреждения «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Российская Федерация

Junior Researcher, Laboratory for Molecular, Translational, and Digital Medicine, Department of Experimental Medicine, Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russian Federation

anastasiakanonykina@gmail.comhttps://orcid.org/0000-0002-1867-6354ЛазебнаяАнастасия ИвановнаLazebnayaAnastasia I.

младший научный сотрудник лаборатории молекулярной, трансляционной и цифровой медицины отдела экспериментальной медицины федерального государственного бюджетного научного учреждения «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Российская Федерация

Junior Researcher, Laboratory for Molecular, Translational, and Digital Medicine, Department of Experimental Medicine, Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russian Federation

anastasialazebnaa2@gmail.comhttps://orcid.org/0000-0002-4326-7640КондратьевЕгор АндреевичKondratievEgor A.

доктор медицинских наук заведующий отделом экспериментальной медицины федерального государственного бюджетного научного учреждения «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Российская Федерация

Junior Researcher, Laboratory for Molecular, Translational, and Digital Medicine, Department of Experimental Medicine, Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russian Federation

kondr6216@gmail.comhttps://orcid.org/0009-0009-7947-5917СтепановАлександр ДенисовичStepanovAlexander D.

младший научный сотрудник лаборатории молекулярной, трансляционной и цифровой медицины отдела экспериментальной медицины федерального государственного бюджетного научного учреждения «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Российская Федерация

Junior Researcher, Laboratory for Molecular, Translational, and Digital Medicine, Department of Experimental Medicine, Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russian Federation

sasste334@gmail.comhttps://orcid.org/0000-0001-8679-4857КутихинАнтон ГеннадьевичKutikhinAnton G.

младший научный сотрудник лаборатории молекулярной, трансляционной и цифровой медицины отдела экспериментальной медицины федерального государственного бюджетного научного учреждения «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Российская Федерация

PhD, Head of the Department of Experimental Medicine, Federal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Kemerovo, Russian Federation

antonkutikhin@gmail.comФедеральное государственное бюджетное научное учреждение «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний»РоссияFederal State Budgetary Institution “Research Institute for Complex Issues of Cardiovascular Diseases”Russian Federation202401112024133Sприложение191207Copyright © Богданов Л.А., Кошелев В.А., Мухамадияров Р.А., Каноныкина А.Ю., Лазебная А.И., Кондратьев Е.А., Степанов А.Д., Кутихин А.Г., 20242024Богданов Л.А., Кошелев В.А., Мухамадияров Р.А., Каноныкина А.Ю., Лазебная А.И., Кондратьев Е.А., Степанов А.Д., Кутихин А.Г.Bogdanov L.A., Koshelev V.A., Mukhamadiyarov R.A., Kanonykina A.Y., Lazebnaya A.I., Kondratiev E.A., Stepanov A.D., Kutikhin A.G.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nii-kpssz.com/jour/article/view/1526Основные положения

Основные положения

 

 

Резюме

Резюме

В обзоре рассмотрено несколько групп потенциальных клеточных маркеров различных видов дисфункции эндотелия: вазоспастической, провоспалительной и протромботической. Проведен анализ научных данных по исследованию молекул, дифференциально экспрессируемых в дисфункциональных эндотелиальных клетках, приведены результаты ретроспективного анализа соответствующей литературы в базе данных PubMed за последние 45 лет. Иммуногистохимический анализ развития вазоспастической дисфункции эндотелия подразумевает измерение экспрессии эндотелиальной NO-синтазы и ее фосфорилированных форм (серин-113/117, треонин-495, серин-632, серин-1176/1177), механочувствительных транскрипционных факторов (KLF2, KLF4 и NRF2), маркеров нитрозативного стресса (3-нитротирозин и 6-нитротриптофан), маркеров окислительного стресса (связанные с малондиальдегидом или метилглиоксалем белки, ксантиноксидаза и изоформы NADPH-оксидазы NOX1, NOX2, NOX4 и NOX5). В качестве вероятных иммуногистохимических маркеров провоспалительной дисфункции эндотелия предлагаются N-кадгерин как маркер мезенхимальных клеток в сочетании с потерей эндотелиальных маркеров (CD31 и VE-кадгерина), транскрипционные факторы эндотелиально-мезенхимального перехода (Snail, Slug, Twist1 и Zeb1), провоспалительные транскрипционные факторы (NF-κB, IRF1, IRF3, IRF5, IRF7, AP-1, ATF1, ATF2, ATF3, ATF4, ATF6, EGR-1, EGR-3, STAT1, STAT3 и STAT4), NLRP3 как маркер инфламмасом, вышеуказанные механочувствительные транскрипционные факторы, индуцибельные молекулы клеточной адгезии (VCAM1, ICAM1, E-селектин), а также компоненты базальной мембраны (ламинин, коллаген IV типа, нидоген-1, нидоген-2, перлекан, фибронектин) и эндотелиальные интегрины (α2β1, α3β1, α5β1, α9β1, αvβ3, αvβ5). В свою очередь, иммуногистохимический анализ протромботической дисфункции эндотелия может основываться на оценке экспрессии компонентов эндотелиального гликокаликса (при помощи иммунофлуоресцентного окрашивания UEA-1, связывающегося с фукозилированными гликанами, или посредством иммуногистохимического окрашивания на синдекан-1, гепарансульфат, хондроитинсульфат, гиалуроновую кислоту, перлекан и глипикан-1), а также на оценке экспрессии его антитромботических (антитромбин III, ингибитор тканевого фактора, тромбомодулин, CD39, CD73) или протромботических (гепараназа, гиалуронидаза, ангиотензинпревращающий фермент 2, фактор фон Виллебранда) белков. Верификацию иммуногистохимических маркеров, дифференциально экспрессируемых в контрольных и модельных животных, целесообразно осуществлять в ассоциации с электронной микроскопией в обратно рассеянных электронах с целью установления ассоциативных и корреляционных связей между молекулярными маркерами и патоморфологическими изменениями.

Highlights

Highlights

 

 

Abstract

Abstract

This review examines several groups of potential cellular markers for various types of endothelial dysfunction: vasospastic, proinflammatory, and prothrombotic. For this purpose, we screened the PubMed database for the respective publications over the past 45 years. Immunohistochemical analysis of the development of vasospastic endothelial dysfunction involves measuring the expression of endothelial NO synthase and its phosphorylated forms (serine-113/117, threonine-495, serine-632, serine-1176/1177), mechanosensitive transcription factors (KLF2, KLF4, and NRF2), markers of nitrosative stress (3-nitrotyrosine and 6-nitrotryptophan), and oxidative stress markers (proteins associated with malondialdehyde or methylglyoxal, xanthine oxidase, and isoforms of NADPH oxidase NOX1, NOX2, NOX4, and NOX5). Potential immunohistochemical markers of proinflammatory endothelial dysfunction include N-cadherin as a mesenchymal cell marker in combination with the loss of endothelial markers (CD31 and VE-cadherin), transcription factors of endothelial-mesenchymal transition (Snail, Slug, Twist1, and Zeb1), proinflammatory transcription factors (NF-κB, IRF1, IRF3, IRF5, IRF7, AP-1, ATF1, ATF2, ATF3, ATF4, ATF6, EGR-1, EGR-3, STAT1, STAT3, and STAT4), NLRP3 as a marker of inflammasomes, the aforementioned mechanosensitive transcription factors, inducible cell adhesion molecules (VCAM1, ICAM1, E-selectin), as well as components of the basement membrane (laminin, type IV collagen, nidogen-1, nidogen-2, perlecan, fibronectin) and endothelial integrins (α2β1, α3β1, α5β1, α9β1, αvβ3, αvβ5). Immunohistochemical analysis of prothrombotic endothelial dysfunction may rely on assessing the expression of components of the endothelial glycocalyx (via immunofluorescent staining with UEA-1, which binds to fucosylated glycans, or through immunohistochemical staining for syndecan-1, heparan sulfate, chondroitin sulfate, hyaluronic acid, perlecan, and glypican-1), as well as evaluating the expression of its antithrombotic (antithrombin III, tissue factor inhibitor, thrombomodulin, CD39, CD73) or prothrombotic proteins (heparanase, hyaluronidase, angiotensin-converting enzyme 2, von Willebrand factor). Verification of immunohistochemical markers differentially expressed in control and model animals should be conducted using electron microscopy of adjacent vascular segments to establish associative and correlative relationships between molecular and pathomorphological markers.

Эндотелиальные клеткиФизиология эндотелияДисфункция эндотелияВоспалениеКлеточные маркерыИммуногистохимияЭлектронная микроскопияEndothelial cellsEndothelial physiologyEndothelial dysfunctionInflammationCellular markersImmunohistochemistryElectron microscopyИсследование выполнено за счет гранта Российского научного фонда № 24-75-10057 «Идентификация клеточных маркеров дисфункции эндотелия», https://rscf.ru/project/24-75-10057/.This research was funded by the Russian Science Foundation, grant number 24-75-10057 “Cellular markers of endothelial dysfunction” (Leo Bogdanov), https://rscf.ru/project/24-75-10057/.ReferencesAlexander Y., Osto E., Schmidt-Trucksäss A., Shechter M., Trifunovic D., Duncker D.J., Aboyans V., Bäck M., Badimon L., Cosentino F., De Carlo M., Dorobantu M., Harrison D.G., Guzik T.J., Hoefer I., Morris P.D., Norata G.D., Suades R., Taddei S., Vilahur G., Waltenberger J., Weber C., Wilkinson F., Bochaton-Piallat M.L., Evans P.C. 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The authors declare that there are no conflicts of interest present.