sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.18699/SSMJ20220604sibmed-932Research ArticleМЕДИКО-БИОЛОГИЧЕСКИЕ НАУКИBIOMEDICINEИндукторы системы Keap1/Nrf2/ARE не увеличивают устойчивость сердца к длительной ишемии/реперфузииThe Keap1/Nrf2/ARE system activators do not increase cardiac resistance to long-term ischemia/reperfusionhttps://orcid.org/0000-0002-9989-9778КожинП. М.KozhinP. M.

Пётр Михайлович Кожин, к.м.н.

630117, Новосибирск, ул. Тимакова, 2

Peter M. Kozhin, candidate of medical sciences

630117, Novosibirsk, Timakov str., 2

kozhinpm@gmail.comhttps://orcid.org/0000-0002-6991-4930СеменцовА. С.SementsovA. S.

Андрей Сергеевич Семенцов

634012, г. Томск, ул. Киевская, 111А

Andrey S. Sementsov

634012, Tomsk, Kievskaya str., 111A

hamkot@sibmail.comХраповС. Е.KhrapovS. E.

Семён Евгеньевич Храпов

630117, Новосибирск, ул. Тимакова, 2

Semen E. Khrapov

630117, Novosibirsk, Timakov str., 2

semen.hrapov@gmail.comhttps://orcid.org/0000-0003-3397-8067ХраповаМ. В.KhrapovaM. V.

Марина Валерьевна Храпова, к.б.н.

630117, Новосибирск, ул. Тимакова, 2

Marina V. Khrapova, candidate of biological sciences

630117, Novosibirsk, Timakov str., 2

khrapova@centercem.ruРомахЛ. П.RomakhL. P.

Лидия Петровна Ромах

630117, Новосибирск, ул. Тимакова, 2

Lidia P. Romakh

630117, Novosibirsk, Timakov str., 2

lpromakh@centercem.ruhttps://orcid.org/0000-0001-6022-934XКандалинцеваН. В.KandalintsevaN. V.

Наталья Валерьевна Кандалинцева, д.х.н.

630126, г. Новосибирск, ул. Вилюйская, 28

Natalya V. Kandalintseva, doctor of chemical sciences

630126, Novosibirsk, Vilyuiskaya str., 28

aquaphenol@mail.ruhttps://orcid.org/0000-0003-2367-0114МеньщиковаЕ. Б.MenshchikovaE. B.

Елена Брониславовна Меньщикова, д.м.н.

630117, Новосибирск, ул. Тимакова, 2

Elena B. Menshchikova, doctor of medical sciences

630117, Novosibirsk, Timakov str., 2

lemen@centercem.ruФИЦ фундаментальной и трансляционной медициныРоссияFederal Research Center of Fundamental and Translational MedicineRussian FederationНИИ кардиологии Томского национального исследовательского медицинского центра РАНРоссияCardiology Research Institute of Tomsk National Research Medical Center RASRussian FederationНовосибирский государственный педагогический университетРоссияNovosibirsk State Pedagogical UniversityRussian Federation2022261220224263544Copyright © Кожин П.М., Семенцов А.С., Храпов С.Е., Храпова М.В., Ромах Л.П., Кандалинцева Н.В., Меньщикова Е.Б., 20222022Кожин П.М., Семенцов А.С., Храпов С.Е., Храпова М.В., Ромах Л.П., Кандалинцева Н.В., Меньщикова Е.Б.Kozhin P.M., Sementsov A.S., Khrapov S.E., Khrapova M.V., Romakh L.P., Kandalintseva N.V., Menshchikova E.B.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/932

В качестве важного механизма повреждения миокарда при ишемии/реперфузии выступает окислительный стресс. С целью рассмотрения возможности восстановления редокс-баланса с помощью «непрямых» антиоксидантных воздействий изучен кардиопротективный эффект индукторов системы Keap1/Nrf2/ARE при моделировании длительной ишемии/реперфузии in vivo. Материал и методы. Использовали оригинальный синтетический гидрофильный монофенол 3-(3’-трет-бутил-4’-гидроксифенил) пропилтиосульфонат натрия (ТС-13) и препарат сравнения трет-бутилгидрохинон (tBHQ). Самцы крыс линии Вистар в течение 7 сут ежедневно получали по 100 мг/кг раствора ТС-13 (с питьевой водой) или tBHQ (внутрибрюшинно), животные групп сравнения – соответствующие растворители. Через 1 сут после последнего приема препаратов in vivo моделировали локальную ишемию (45 мин, окклюзия левой коронарной артерии) и реперфузию (120 мин) сердца. В течение всего времени ишемии и во время реперфузии регистрировали ЭКГ, по окончании реперфузии сердце извлекали, определяли зону гипоперфузии и зону некроза. Изменение экспрессии в ткани миокарда мРНК генов Nfe2l2, Nqo1, Hmox1, Gstp1, Rela и Nfkb2 определяли методом TaqMan ПЦР в режиме реального времени. Результаты и их обсуждение. Установлено, что группы крыс, получавших ТС-13 и tBHQ, по величине зон некроза и количеству нарушений ритма не отличались от соответствующих контрольных групп. Предварительное введение животным tBHQ не изменяло экспрессию исследуемых генов в ткани сердца после длительной ишемии/реперфузии. Назначение ТС-13 сопровождалось увеличением содержания транскриптов гена, кодирующего Nrf2 (в 7,64 раза), и подконтрольных ему генов Nqo1 (в 6,46 раза) и Hmox1 (в 3,63 раза); экспрессия генов Gstp1, Rela и Nfkb2 не отличалась от соответствующих величин группы контроля; по сравнению с животными, получавшими tBHQ, экспрессия генов Nfe2l2, Nqo1, Hmox1, Rela и Nfkb2 была больше соответственно в 16,23, 4,44, 2,68, 3,17 и 2,64 раза. Полученные результаты ставят под сомнение терапевтическую значимость индукции системы Keap1/ Nrf2/ARE при длительной ишемии/реперфузии сердца.

Oxidative stress is an important mechanism of myocardial damage during ischemia/reperfusion. To investigate the possibility of restoring the redox balance using “indirect” antioxidant effects, the cardioprotective effect Keap1/Nrf2/ ARE system inducers was studied in long-term ischemia/reperfusion in vivo. Material and methods. We used the original synthetic hydrophilic monophenol sodium 3-(3’-tert-butyl-4’-hydroxyphenyl) propyl thiosulfonate (TS-13) and reference drug tert-butylhydroquinone (tBHQ). Male Wistar rats received 100 mg/kg of TS-13 solution (with drinking water) or tBHQ (intraperitoneally) daily for 7 days. Animals of the comparison groups received the corresponding solvents. Local ischemia (45 min, occlusion of the left coronary artery) and reperfusion (120 min) of the heart were simulated in vivo 1 day after last drug administration. The ECG was recorded during ischemia and reperfusion; at the end of reperfusion, the heart was removed, the zone of hypoperfusion and the zone of necrosis were detected. Changes in the expression of the mRNA of Nfe2l2, Nqo1, Hmox1, Gstp1, Rela, and Nfkb2 gene in myocardial tissue were determined by real-time TaqMan PCR. Results and discussion. Pretreatment with TS-13 and tBHQ did not influence the infarct size and the incidence of ventricular arrhythmias. Preliminary administration of tBHQ did not change the genes expression of the studied in myocardial tissue after prolonged I/R. TS-13 administration was accompanied by an increase in the content of the transcripts of the gene that encodes Nrf2 (by 7.64 times) and Nrf2-driven genes Nqo1 (by 6.46 times) and Hmox1 (by 3.63 times); the expression of the Gstp1, Rela, and Nfkb2 genes did not differ from the corresponding values of the control group; compared to animals treated with tBHQ, the expression of the Nfe2l2, Nqo1, Hmox1, Rela, and Nfkb2 genes was 16.23, 4.44, 2.68, 3.17, and 2.64 times higher, respectively. The results obtained cast doubt on the therapeutic importance of the induction of the Keap1/Nrf2/ARE system during prolonged heart ischemia/reperfusion.

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