scbmtБИОМЕДИЦИНАJournal Biomed2074-59822713-0428Scientific center of biomedical technologies of Federal Medical and Biological Agency10.33647/2074-5982-18-2-52-62scbmt-1388Research ArticleБИОРЕГУЛЯТОРЫ В МЕДИЦИНСКИХ ТЕХНОЛОГИЯХBIOREGULATORS IN MEDICAL TECHNOLOGIESВлияние интраназально вводимого инсулина на Na+/K+-АТФазу и компоненты Са2+-транспортирующей системы в кардиомиоцитах у крыс с сахарным диабетом 1-го типаImpact of Intranasal Insulin Administration On Na+/K+-Atpase and Са2+-Transporting System Components in Rat Cardiomyocytes with Type 1 Diabetes MellitusСуховИ. Б.SukhovI. B.

 к.б.н.,

 194223, Российская Федерация, Санкт-Петербург, просп. Тореза, 44 

 Cand. Sci. (Biol.), 

 194223, Russian Federation, Saint-Petersburg, Thorez Ave., 44 

sukhov.ivan@gmail.comЧистяковаО. В.ChistyakovaO. V.

 к.б.н., 

 194223, Российская Федерация, Санкт-Петербург, просп. Тореза, 44 

 Cand. Sci. (Biol.), 

 194223, Russian Federation, Saint-Petersburg, Thorez Ave., 44 

chiosana@yandex.ruФГБУН «Институт эволюционной физиологии и биохимии им. И.М. Сеченова» РАНРоссияSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesRussian Federation2022100620221825262Copyright © Сухов И.Б., Чистякова О.В., 20222022Сухов И.Б., Чистякова О.В.Sukhov I.B., Chistyakova O.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.scbmt.ru/jour/article/view/1388

В условиях сахарного диабета 1-го типа (СД1) часто развиваются тяжёлые формы сердечно-сосудистой патологии. Для коррекции функций сердечно-сосудистой системы могут быть использованы подходы, ослабляющие провоспалительные и антиапоптотические сигналы вовлечённых в патологическую гипертрофию кардиомиоцитов и повышающие активность кардиопротекторных путей в них. Поскольку при СД1 ослабляется инсулиновая система мозга, вовлечённая в контроль сердечно-сосудистой системы и функций кардиомиоцитов, то одним из таких подходов является применение интраназально вводимого инсулина (ИВИ). Целью работы было изучить влияние ИВИ на экспрессию генов, кодирующих компоненты инсулиновой системы и Са2+-транспортирующей системы, а также активность Na+/К+-АТФазы в кардиомиоцитах крыс со стрептозотоциновым СД1. ИВИ устранял возникающее при СД1 разобщение молекулярных механизмов, участвующих в электромеханическом сопряжении в кардиомиоцитах крыс. Это указывает на перспективность дальнейших исследований ИВИ как препарата, потенциально способного восстанавливать функции миокарда при СД1.

Cardiovascular pathology is the main cause of morbidity among patients with diabetes mellitus. The development of a specific therapy aimed at either blunting the protein signals involved in pathological cardiomyocyte hypertrophy or upregulating the expression of cardioprotective pathways can support new strategies for treating diabetes-induced cardiac dysfunctions. The aim of the work was to study the impact of intranasal insulin administration (IIA) on the expression of genes encoding insulin-dependent signaling proteins and components of the Ca2+-transporting system, as well as on the activity of Na+/K+-ATPase in cardiomyocytes on the model of experimental type 1 diabetes mellitus (DM1) in rats. It was shown that IIA eliminates the uncoupling of molecular mechanisms involved in electromechanical coupling in rat cardiomyocytes that occurs under the conditions of mild DM1. This allowed us to recommend IIA as a therapeutic approach to the prevention and treatment of structural and functional myocardial disorders caused by diabetes.

сердцесахарный диабетдиабетическая кардиомиопатияNa+/K+-АТФазаинтраназально введённый инсулинкрысаheartdiabetes mellitusdiabetic cardiomyopathyNa+/K+-ATPaseintranasally administered insulinratФинансирование: средства государственного бюджета Минобрнауки России по госзаданию 075-00886-20-01 (направление АААА-А18-118012290427) с использованием оборудования ЦКП ИЭФБ РАН. Благодарности: авторы выражают благодарность профессору МГУ Ольге Сергеевне Тарасовой за обсуждение идей статьи.Funding: State budget funds of the Ministry of Science and Higher Education assignment No. 075- 00886-20-01 (direction AAAA-A18-118012290427) using the equipment of the Center for Collective Use of the IEPhB RAS. Acknowledgment: The authors express their appreciation to Olga Sergeevna Tarasova, Prof. of Moscow State University, for discussing the ideas presented in the article.ReferencesЧистякова О.В., Сухов И.Б., Добрецов М.Г., Кубасов И.В. Изучение активности NA/K-атфазы в миокарде крыс в экспериментальных условиях преддиабета и сахарного диабета. Журнал эволюционной биохимии и физиологии. 2020;56(2):166–168. DOI: 10.31857/S0044452920020047.Chistyakova O.V., Sukhov I.B., Dobretsov M.G., Kubasov I.V. Izuchenie aktivnosti NA/K-atfazy` v miokarde kry`s v e`ksperimental`ny`x usloviyax preddiabeta i saxarnogo diabeta [The study of rat myocardial Na/K-ATPase activity in experimental conditions of prediabetes and diabetes mellitus]. Zhurnal evolyutsionnoy biokhimii i fiziologii [Journal of Evolutionary Biochemistry and Physiology]. 2020;56(2):166–168. (In Russian). DOI: 10.31857/S0044452920020047.Andersson U., Tracey K.J. Reflex principles of immunological homeostasis. Annu. Rev. Immunol.БИОМЕДИЦИНА | JOURNAL BIOMED | 2022 | Toм 18 | № 2 | 52–62 61 2012;30:313–335. DOI: 10.1146/annurev-immunol-020711-075015.Andersson U., Tracey K.J. Reflex principles of immunological homeostasis. Annu. Rev. Immunol.БИОМЕДИЦИНА | JOURNAL BIOMED | 2022 | Toм 18 | № 2 | 52–62 61 2012;30:313–335. DOI: 10.1146/annurev-immunol-020711-075015.Berry R.G., Despa S., Fuller W., Bers D.M., Shattock M.J. Differential distribution and regulation of mouse cardiac Na+/K+-ATPase α1 and α2 subunits in T-tubule and surface sarcolemmal membranes. Cardiovasc. Res. 2007;73(1):92–100. DOI: 10.1016/j.cardiores.2006.11.006Berry R.G., Despa S., Fuller W., Bers D.M., Shattock M.J. Differential distribution and regulation of mouse cardiac Na+/K+-ATPase α1 and α2 subunits in T-tubule and surface sarcolemmal membranes. Cardiovasc. Res. 2007;73(1):92–100. DOI: 10.1016/j.cardiores.2006.11.006Blake C.B., Smith B.N. Insulin reduces excitation in gastric-related neurons of the dorsal motor nucleus of the vagus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012;303(8):R807–R814. DOI: 10.1152/ajpregu.00276.2012.Blake C.B., Smith B.N. Insulin reduces excitation in gastric-related neurons of the dorsal motor nucleus of the vagus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012;303(8):R807–R814. DOI: 10.1152/ajpregu.00276.2012.Bublitz M. (ed.). P-type ATPases: Methods and protocols, methods in molecular biology. New York: Springer Science+Business Media, 2016;1377.Bublitz M. (ed.). P-type ATPases: Methods and protocols, methods in molecular biology. New York: Springer Science+Business Media, 2016;1377.Chibalin A.V. Regulation of the Na,K-ATPase: Special implications for cardiovascular complications of metabolic syndrome. Pathophysiology. 2007;14(3–4):153–158. DOI: 10.1016/j.pathophys.2007.09.004.Chibalin A.V. Regulation of the Na,K-ATPase: Special implications for cardiovascular complications of metabolic syndrome. Pathophysiology. 2007;14(3–4):153–158. DOI: 10.1016/j.pathophys.2007.09.004.Dallak M., Al-Ani B., Abdel Kader D.H., Eid R.A., Haidara M.A. Insulin suppresses type 1 diabetes mellitus-induced ventricular cardiomyocyte damage associated with the inhibition of biomarkers of inflammation and oxidative stress in rats. Pharmacology. 2019;104(3–4):157–165. DOI: 10.1159/000500898.Dallak M., Al-Ani B., Abdel Kader D.H., Eid R.A., Haidara M.A. Insulin suppresses type 1 diabetes mellitus-induced ventricular cardiomyocyte damage associated with the inhibition of biomarkers of inflammation and oxidative stress in rats. Pharmacology. 2019;104(3–4):157–165. DOI: 10.1159/000500898.Despa S., Bers D.M. Functional analysis of Na/KATPase isoform distribution in rat ventricular myocytes. Am. J. Physiol. Cell Physiol. 2007;293(1):C321–C327. DOI: 10.1152/ajpcell.00597.2006.Despa S., Bers D.M. Functional analysis of Na/KATPase isoform distribution in rat ventricular myocytes. Am. J. Physiol. Cell Physiol. 2007;293(1):C321–C327. DOI: 10.1152/ajpcell.00597.2006.Despa S., Lingrel J.B., Bers D.M. Na(+)/K)+)-ATPase α2-isoform preferentially modulates Ca2(+) transients and sarcoplasmic reticulum Ca2(+) release in cardiac myocytes. Cardiovasc. Res. 2012;95(4):480–486. DOI: 10.1093/cvr/cvs213.Despa S., Lingrel J.B., Bers D.M. Na(+)/K)+)-ATPase α2-isoform preferentially modulates Ca2(+) transients and sarcoplasmic reticulum Ca2(+) release in cardiac myocytes. Cardiovasc. Res. 2012;95(4):480–486. DOI: 10.1093/cvr/cvs213.Hang P., Zhao J., Qi J., Wang Y., Wu J., Du Z. Novel insights into the pervasive role of M(3) muscarinic receptor in cardiac diseases. Curr. Drug Targets. 2013;14(3):372–377.Hang P., Zhao J., Qi J., Wang Y., Wu J., Du Z. Novel insights into the pervasive role of M(3) muscarinic receptor in cardiac diseases. Curr. Drug Targets. 2013;14(3):372–377.Hansen P.S., Buhagiar K.A., Gray D.F., Rasmussen H.H. Voltage-dependent stimulation of the Na(+)-K(+) pump by insulin in rabbit cardiac myocytes. Am. J. Physiol. Cell. Physiol. 2000;278(3):C546–С553. DOI: 10.1152/ajpcell.2000.278.3.C546.Hansen P.S., Buhagiar K.A., Gray D.F., Rasmussen H.H. Voltage-dependent stimulation of the Na(+)-K(+) pump by insulin in rabbit cardiac myocytes. Am. J. Physiol. Cell. Physiol. 2000;278(3):C546–С553. DOI: 10.1152/ajpcell.2000.278.3.C546.Iannello S., Milazzo P., Belfiore F. Animal and human tissue Na, K-ATPase in obesity and diabetes: A new proposed enzyme regulation. Am. J. Med. Sci. 2007;333(1):1–9. DOI: 10.1097/00000441-200701000-00001.Iannello S., Milazzo P., Belfiore F. Animal and human tissue Na, K-ATPase in obesity and diabetes: A new proposed enzyme regulation. Am. J. Med. Sci. 2007;333(1):1–9. DOI: 10.1097/00000441-200701000-00001.Krowicki Z.K., Nathan N.A., Hornby P.J. Gastric motor and cardiovascular effects of insulin in dorsal vagal complex of the rat. Am. J. Physiol. 1998;275(5):G964–G972. DOI: 10.1152/ajpgi.1998.275.5.G964.Krowicki Z.K., Nathan N.A., Hornby P.J. Gastric motor and cardiovascular effects of insulin in dorsal vagal complex of the rat. Am. J. Physiol. 1998;275(5):G964–G972. DOI: 10.1152/ajpgi.1998.275.5.G964.Lochhead J.J., Thorne R.G. Intranasal delivery of biologics to the central nervous system. Adv. Drug Deliv. Rev. 2012;64(7):614-628. DOI: 10.1016/j.addr.2011.11.002.Lochhead J.J., Thorne R.G. Intranasal delivery of biologics to the central nervous system. Adv. Drug Deliv. Rev. 2012;64(7):614-628. DOI: 10.1016/j.addr.2011.11.002.Louch W.E., Sejersted O.M., Swift F. There goes the neighborhood: Pathological alterations in T-tubule morphology and consequences for cardiomyocyte Ca2+ handling. J. Biomed. Biotechnol. 2010;2010:503906. DOI: 10.1155/2010/503906.Louch W.E., Sejersted O.M., Swift F. There goes the neighborhood: Pathological alterations in T-tubule morphology and consequences for cardiomyocyte Ca2+ handling. J. Biomed. Biotechnol. 2010;2010:503906. DOI: 10.1155/2010/503906.Machhada A., Hosford P.S., Dyson A., Ackland G.L., Mastitskaya S., Gourine A.V. Optogenetic stimulation of vagal efferent activity preserves left ventricular function in experimental heart failure. JACC Basic Transl. Sci. 2020;5(8):799–810. DOI: 10.1016/j.jacbts.2020.06.002.Machhada A., Hosford P.S., Dyson A., Ackland G.L., Mastitskaya S., Gourine A.V. Optogenetic stimulation of vagal efferent activity preserves left ventricular function in experimental heart failure. JACC Basic Transl. Sci. 2020;5(8):799–810. DOI: 10.1016/j.jacbts.2020.06.002.Olofsson P.S., Rosas-Ballina M., Levine Y.A., Tracey K.J. Rethinking inflammation: Neural circuits in the regulation of immunity. Immunol. Rev. 2012;248(1):188–204. DOI: 10.1111/j.1600-065X.2012.01138.x.Olofsson P.S., Rosas-Ballina M., Levine Y.A., Tracey K.J. Rethinking inflammation: Neural circuits in the regulation of immunity. Immunol. Rev. 2012;248(1):188–204. DOI: 10.1111/j.1600-065X.2012.01138.x.Pan Z., Guo Y., Qi H., Fan K., Wang S., Zhao H., Fan Y., Xie J., Guo F., Hou Y., Wang N., Huo R., Zhang Y., Liu Y., Du Z. M3 subtype of muscarinic acetylcholine receptor promotes cardioprotection via the suppression of miR-376b-5p. PLoS One. 2012;7(3):e32571. DOI: 10.1371/journal.pone.0032571.Pan Z., Guo Y., Qi H., Fan K., Wang S., Zhao H., Fan Y., Xie J., Guo F., Hou Y., Wang N., Huo R., Zhang Y., Liu Y., Du Z. M3 subtype of muscarinic acetylcholine receptor promotes cardioprotection via the suppression of miR-376b-5p. PLoS One. 2012;7(3):e32571. DOI: 10.1371/journal.pone.0032571.Pocai A., Lam T.K., Gutierrez-Juarez R., Obici S., Schwartz G.J., Bryan J., Aguilar-Bryan L., Rossetti L. Hypothalamic K(ATP) channels control hepatic glucose production. Nature. 2005;434(7036):1026–1031. DOI: 10.1038/nature03439.Pocai A., Lam T.K., Gutierrez-Juarez R., Obici S., Schwartz G.J., Bryan J., Aguilar-Bryan L., Rossetti L. Hypothalamic K(ATP) channels control hepatic glucose production. Nature. 2005;434(7036):1026–1031. DOI: 10.1038/nature03439.Romic S., Djordjevic A., Tepavcevic S., Culafic T., Stojiljkovic M., Bursac B., Stanisic J., Kostic M., Gligorovska L., Koricanac G. Effects of a fructose-rich diet and chronic stress on insulin signaling and regulation of glycogen synthase kinase-3 beta and the sodium-potassium pump in the hearts of male rats. Food Funct. 2020;11(2):1455–1466. DOI: 10.1039/c9fo02306b.Romic S., Djordjevic A., Tepavcevic S., Culafic T., Stojiljkovic M., Bursac B., Stanisic J., Kostic M., Gligorovska L., Koricanac G. Effects of a fructose-rich diet and chronic stress on insulin signaling and regulation of glycogen synthase kinase-3 beta and the sodium-potassium pump in the hearts of male rats. Food Funct. 2020;11(2):1455–1466. DOI: 10.1039/c9fo02306b.Rosta K., Tulassay E., Enzsoly A., Ronai K., Szantho A., Pandics T., Fekete A., Mandl P., Ver A. Insulin induced translocation of Na+/K+ -ATPase is decreased in the heart of streptozotocin diabetic rats. Acta Pharmacol. Sin. 2009;30(12):1616–1624. DOI: 10.1038/aps.2009.162.Rosta K., Tulassay E., Enzsoly A., Ronai K., Szantho A., Pandics T., Fekete A., Mandl P., Ver A. Insulin induced translocation of Na+/K+ -ATPase is decreased in the heart of streptozotocin diabetic rats. Acta Pharmacol. Sin. 2009;30(12):1616–1624. DOI: 10.1038/aps.2009.162.Shpakov A.O., Derkach K.V., Chistyakova O.V., Moiseyuk I.V., Sukhov I.B., Bondareva V.M. Effect of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in myocardium, ovary, and uterus of rats with prolonged neonatal model of diabetes mellitus. J. Evol. Biochem. Physiol. 2013;49(2):153–164. DOI: 10.1134/S0022093013020047.Shpakov A.O., Derkach K.V., Chistyakova O.V., Moiseyuk I.V., Sukhov I.B., Bondareva V.M. Effect of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in myocardium, ovary, and uterus of rats with prolonged neonatal model of diabetes mellitus. J. Evol. Biochem. Physiol. 2013;49(2):153–164. DOI: 10.1134/S0022093013020047.Shpakov A.O., Chistyakova O.V., Derkach K.V., Moiseyuk I.V., Bondareva V.M. Intranasal insulin affects adenylyl cyclase system in rat tissues in neonatal diabetes. Central Eur. J. Biol. 2012;7(1):33–47. DOI: 10.2478/s11535-011-0089-6.Shpakov A.O., Chistyakova O.V., Derkach K.V., Moiseyuk I.V., Bondareva V.M. Intranasal insulin affects adenylyl cyclase system in rat tissues in neonatal diabetes. Central Eur. J. Biol. 2012;7(1):33–47. DOI: 10.2478/s11535-011-0089-6.Ver A., Szántó I., Bányász T., Csermely P., Végh E., Somogyi J. Changes in the expression of Na+/K+-ATPase isoenzymes in the left ventricle of diabetic rat hearts: effect of insulin treatment. Diabetologia. 1997;40(11):1255–1262. DOI: 10.1007/s001250050818.Ver A., Szántó I., Bányász T., Csermely P., Végh E., Somogyi J. Changes in the expression of Na+/K+-ATPase isoenzymes in the left ventricle of diabetic rat hearts: effect of insulin treatment. Diabetologia. 1997;40(11):1255–1262. DOI: 10.1007/s001250050818.Yan X., Xun M., Dou X., Wu L., Han Y., Zheng J. Regulation of Na+-K+-ATPase effected high glucose-induced myocardial cell injury through c-Src dependent NADPH oxidase/ROS pathway. Exp. Cell Res. 2017;357(2):243–251. DOI: 10.1016/j.yexcr.2017.05.023.Yan X., Xun M., Dou X., Wu L., Han Y., Zheng J. Regulation of Na+-K+-ATPase effected high glucose-induced myocardial cell injury through c-Src dependent NADPH oxidase/ROS pathway. Exp. Cell Res. 2017;357(2):243–251. DOI: 10.1016/j.yexcr.2017.05.023.

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