Триггерный Cа²⁺-зависимый механизм ранних возрастных нарушений сократительной функции сердца у крыс самцов и самок
Ключевые слова:
старение, половой диморфизм, экспрессия, сердце, рианодиновые рецепторы, RyR2, инози тол-145-трисфосфатные рецепторы, IP3 R, кальмодулин, Epac2, CaV1.2 KV1.1 1.3 1.6 каналы, SERCA2, фосфоламбан
Аннотация
Возрастные структурные и функциональные изменения в сердце мужчин диагностируются раньше, чем у женщин. Особенности механизмов, лежащих в основе половых различий развития возраст-ассоциированной электрической нестабильности и нарушения сократительной активности миокарда, остаются недостаточно изученными. Цель исследования – изучить половые особенности возрастных изменений транскрипционной активности генов белков наиболее значимых для поддержания электрической стабильности и сократительной функции миокарда – CaV1.2, KV1 каналов, рецепторов IP3R и RyR2, белков SERCA, Plamb, СаМ и Epac2. Материалы и методы: Работу проводили на самцах и самках крыс породы Wistar в возрасте 4 и 18 мес. Методом ПЦР анализа, в предсердиях и левом желудочке молодых и пожилых крыс оценивали экспрессию генов, кодирующих вышеперечисленные белки. Результаты: У крыс самцов старение ассоциировано с более выраженными нарушениями экспрессии белков, участвующих в регуляции кальциевого обмена, чем у самок. В левом желудочке и предсердиях стареющих самцов выявлен значительный рост экспрессии генов белков потенциал-зависимых CaV1.2, KV1.1 каналов, рианодиновых RyR2 и инозитол-трисфосфатных IP3R1,2,3 рецепторов и регуляторов их активности – кальмодулина, Epac2, а также Ca2+-АТФазы SERCA2 и фосфоламбана. У самок возрастные изменения экспрессии исследуемых генов в левом желудочке были минимальными: отмечено лишь повышение уровня мРНК белков Epac2 и CaM и, напротив, снижение RyR2 и IP3R3. Основные отклонения от показателей молодых самок выявлены в предсердиях, главным образом в правом: гиперэкспрессия каналов KV1.1 и CaV1.2, рецепторов RyR2, IP3R1, IP3R3 и белков Epac2 и CaM. У крыс обоего пола отмечено многократное снижение уровня мРНК каналов KV1.6 типа. Заключение. Предположено, что триггерным механизмом возникновения ранних возрастных нарушений сердечного ритма и сократимости миокарда являются изменения транскрипционной активности генов, участвующих в регуляции кальциевого гомеостаза и электрической активности миокарда. Выраженность этих изменений в большей мере проявляется у особей мужского пола.
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Литература
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6. Cannatà A., Fabris E., Merlo M., Artico J., Gentile P., Pio Loco C., Ballaben A., Ramani F., Barbati G., Sinagra G. Sex Differences in the Long-term Prognosis of Dilated Cardiomyopathy. Can. J. Cardiol. 2020; 36(1): 37–44. https://doi.org/10.1016/j.cjca.2019.05.031
7. Kavousi M. Differences in Epidemiology and Risk Factors for Atrial Fibrillation Between Women and Men. Front. Cardiovasc. Med. 2020; 7: 3. https://doi.org/10.3389/fcvm.2020.00003
8. Qian N., Jin J., Gao Y., Liu J., Wang Y. Sex Differences in Atrial Fibrillation: Evidence from Circulating Metabolites. Metabolites 2025; 15(3): 170. https://doi.org/10.3390/metabo15030170
9. Karamnov S., Sarkisian N., Wollborn J., Justice S., Fields K., Kovacheva V.P., Osho A.A., Sabe A., Body S.C., Muehlschlegel J.D. Sex, Atrial Fibrillation, and Long-Term Mortality After Cardiac Surgery. JAMA Netw. Open 2024; 7(8): e2426865. https://doi.org/10.1001/jamanetworkopen.2024.26865
10. Tsuneda T., Yamashita T., Kato T., Sekiguchi A., Sagara K., Sawada H., Aizawa T., Fu L.T., Fujiki A., Inoue H. Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model. J. Cardiovasc. Electrophysiol. 2009; 20(9): 1055–1060. https://doi.org/10.1111/j.1540-8167.2009.01474.x
11. Tykocki N.R., Boerman E.M., Jackson W.F. Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles. Compr. Physiol. 2017; 7(2): 485–581. https://doi.org/10.1002/cphy.c160011
12. Garcia M.I., Karlstaedt A., Chen J.J., Amione-Guerra J., Youker K.A., Taegtmeyer H., Boehning D. Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors. J. Mol. Cell Cardiol. 2017; 112: 95–103. https://doi.org/10.1016/j.yjmcc.2017.09.006
13. Dulhunty A.F., Beard N.A., Casarotto M.G. Recent advances in understanding the ryanodine receptor calcium release channels and their role in calcium signalling. F1000Res. 2018; 7: F1000 Faculty Rev-1851. https://doi.org/10.12688/f1000research.16434.1
14. Mangla A., Guerra M.T., Nathanson M.H. Type 3 inositol 1,4,5-trisphosphate receptor: A calcium channel for all seasons. Cell Calcium 2020; 85: 102132. https://doi.org/10.1016/j.ceca.2019.102132
15. Demydenko K., Ekhteraei-Tousi S., Roderick H.L. Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2022; 377(1864): 20210319. https://doi.org/10.1098/rstb.2021.0319
16. Chen M.S., Lee R.T., Garbern J.C. Senescence mechanisms and targets in the heart. Cardiovasc. Res. 2022; 118(5): 1173–1187. https://doi.org/10.1093/cvr/cvab161
17. Seo M.D., Enomoto M., Ishiyama N., Stathopulos P.B., Ikura M. Structural insights into endoplasmic reticulum stored calcium regulation by inositol 1,4,5-trisphosphate and ryanodine receptors. Biochim. Biophys. Acta 2015; 1853(9): 1980–1991. https://doi.org/10.1016/j.bbamcr.2014.11.023
18. Dixon R.E. Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels. Front. Physiol. 2022; 12: 810408. https://doi.org/10.3389/fphys.2021.810408
19. Lee L.C., Maurice D.H., Baillie G.S. Targeting protein-protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease. Future Med. Chem. 2013; 5(4): 451–464. https://doi.org/10.4155/fmc.12.216
20. de Lucia C., Eguchi A., Koch W.J. New Insights in Cardiac β-Adrenergic Signaling During Heart Failure and Aging. Front. Pharmacol. 2018; 9: 904. https://doi.org/10.3389/fphar.2018.00904
21. Hamilton S., Terentyev D. Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart. Int. J. Mol. Sci. 2019; 20(10): 2386. https://doi.org/10.3390/ijms20102386
22. Federico M., Valverde C.A., Mattiazzi A., Palomeque J. Unbalance Between Sarcoplasmic Reticulum Ca²⁺ Uptake and Release: A First Step Toward Ca²⁺ Triggered Arrhythmias and Cardiac Damage. Front. Physiol. 2020; 10: 1630. https://doi.org/10.3389/fphys.2019.01630
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Опубликован
28-10-2025
Как цитировать
Кожевникова Л. М., Суханова И. Ф. Триггерный Cа²⁺-зависимый механизм ранних возрастных нарушений сократительной функции сердца у крыс самцов и самок // Патологическая физиология и экспериментальная терапия. 2025. Т. 69. № 4. С. 5–16.
Выпуск
Раздел
Оригинальные исследования
