Аннотация
Работа посвящена исследованию профиля молекулярных маркеров фиброза при введении крысам стока Wistar различных доз доксорубицина. Работа выполнена на 40 самцах крыс стока Wistar весом 260 ± 19 гр. Животные были разделены на 4 группы: контроль и три опытные группы с определенной частотой введения (6 раз через два дня) и определенной дозой доксорубицина (5, 10, 15 мг/кг, внутрибрюшинно). По окончании введения химиопрепарата наблюдение за животными составляло 2 месяца. На момент окончания исследования у наркотизированных животных осуществляли забор сердца для проведения молекулярных и морфологических исследований. Гистологический, эхокардиографический и молекулярный анализы выявили дозозависимые повреждающие изменения миокарда левого желудочка на фоне воздействия различных доз доксорубицина. Уровень экспрессии TGF-β не отличался от контрольных значений через 2 месяца после окончания введения всех кумулятивных доз химиопрепарата. Однако на данном этапе исследования сохраненная повышенная экспрессия коллагена I, II типа, ET-1, FGF4 и TNF-α, была характерна для животных, получавших максимальную кумулятивную дозу доксорубицина, что может отражать незавершенность процесса формирования фиброзной ткани, а также их активное участие в развитии воспалительных процессов при выраженном кардиотоксическом повреждении на фоне воздействия химиопрепарата. Для животных, получавших 10 мг/кг наблюдалось отсутствие изменений данных молекулярных маркеров фиброза по сравнению с контрольной группой, тогда как у группы животных с минимальной кумулятивной дозой препарата выявилось снижение экспрессии COL I, II типа, ET-1, TNF-α и увеличение уровня FGF4.
Литература
Markham MJ, Wachter K, Agarwal N, Bertagnolli MM, Chang SM, Dale W, Diefenbach CSM, Rodriguez-Galindo C, George DJ, Gilligan TD, Harvey RD, Johnson ML, Kimple RJ, Knoll MA, LoConte N, Maki RG, Meisel JL, Meyerhardt JA, Pennell NA, Rocque GB, Sabel MS, Schilsky RL, Schneider BJ, Tap WD, Uzzo RG, Westin SN (2020) Clinical Cancer Advances 2020: Annual report on progress against cancer from the American Society of Clinical oncology. J Clin Oncol 38:1081–1101. https://doi.org/10.1200/JCO.19.03141
de Martel C, Georges D, Bray F, Ferlay J, Clifford GM (2020) Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob Heal 8:e180–e190. https://doi.org/10.1016/S2214-109X(19)30488-7
Alam SR, Shah ASV, Richards J, Lang NN, Barnes G, Joshi N, MacGillivray T, McKillop G, Mirsadraee S, Payne J, Fox KAA, Henriksen P, Newby DE, Semple SIK (2012) Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction early clinical experience. Circ Cardiovasc Imaging 5:559–565. https://doi.org/10.1161/CIRCIMAGING.112.974907
Oudard S (2013) Progress in emerging therapies for advanced prostate cancer. Cancer Treat Rev 39:275–289. https://doi.org/10.1016/j.ctrv.2012.09.005
Weingart SN, Zhang L, Sweeney M, Hassett M (2018) Chemotherapy medication errors. Lancet Oncol 19:e191–e199. https://doi.org/10.1016/S1470-2045(18)30094-9
Springfeld C, Jäger D, Büchler MW, Strobel O, Hackert T, Palmer DH, Neoptolemos JP (2019) Chemotherapy for pancreatic cancer. Press Medicale 48:e159–e174. https://doi.org/10.1016/j.lpm.2019.02.025
Knezevic CE, Clarke W (2020) Cancer Chemotherapy: The Case for Therapeutic Drug Monitoring. Ther Drug Monit 42:6–19. https://doi.org/10.1097/FTD.0000000000000701
Renu K, Abilash VG, Tirupathi TP, Arunachalam S (2018) Molecular mechanism of doxorubicin-induced cardiomyopathy – An update. Eur J Pharmacol 818:241–253. https://doi.org/10.1016/j.ejphar.2017.10.043
Hole LD, Larsen TH, Fossan KO, Limé F, Schjøtt J (2013) A short-time model to study relevant indices of cardiotoxicity of doxorubicin in the rat. Toxicol Mech Methods 23:412–418. https://doi.org/10.3109/15376516.2013.773391
Towbin JA, Bowles NE (2002) The failing heart. Nature 415:227–233. https://doi.org/10.1038/415227a
Харина ВИ, Бережнова ТА, Резникова КМ, Брездынюк АД (2017) Способ выявления начальных кардиотоксических эффектов доксорубицина. Вестник новых медицинских технологий 4:165–170. [Kharina VI, Berezhnova TA, Reznikova KM, Brezdynyuk AD (2017) A method for detecting the initial cardiotoxic effects of doxorubicin. Bulletin of new medical technologies 4:165–170. (In Russ)]. https://doi.org/10.12737/article_5a32124941da88.60854778
Mawad W, Mertens L, Pagano JJ, Riesenkampff E, Reichert MJE, Mital S, Kantor PF, Greenberg M, Liu P, Nathan PC, Grosse-Wortmann L (2021) Effect of anthracycline therapy on myocardial function and markers of fibrotic remodelling in childhood cancer survivors. Eur Heart J Cardiovasc Imaging 22:435–442. https://doi.org/10.1093/ehjci/jeaa093
Songbo M, Lang H, Xinyong C, Bin X, Ping Z, Liang S (2019) Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett 307:41–48. https://doi.org/10.1016/j.toxlet.2019.02.013
Zhang YJ, Huang H, Liu Y, Kong B, Wang G (2019) MD-1 deficiency accelerates myocardial inflammation and apoptosis in doxorubicin-induced cardiotoxicity by activating the TLR4/MAPKs/nuclear factor kappa B (NF-kB) signaling pathway. Med Sci Monit 25:7898–7907. https://doi.org/10.12659/MSM.919861
Fu HY, Sanada S, Matsuzaki T, Liao Y, Okuda K, Yamato M, Tsuchida S, Araki R, Asano Y, Asanuma H, Asakura M, French BA, Sakata Y, Kitakaze M, Minamino T (2016) Chemical endoplasmic reticulum chaperone alleviates doxorubicin-induced cardiac dysfunction. Circ Res 118:798–809. https://doi.org/10.1161/CIRCRESAHA.115.307604
Minotti G, Recalcati S, Mordente A, Liberi G, Calafiore AM, Mancuso C, Preziosi P, Cairo G (1998) The secondary alcohol metabolite of doxorubicin irreversibly inactivates aconitase/iron regulatory protein‐1 in cytosolic fractions from human myocardium. FASEB J 12:541–552. https://doi.org/10.1096/fasebj.12.7.541
Pan JA, Tang Y, Yu JY, Zhang H, Zhang JF, Wang CQ, Gu J (2019) miR-146a attenuates apoptosis and modulates autophagy by targeting TAF9b/P53 pathway in doxorubicin-induced cardiotoxicity. Cell Death Dis 10:1–15. https://doi.org/10.1038/s41419-019-1901-x
Miklishanskaya SV, Mazur NA, Shestakova NV (2017) Mechanisms for the formation myocardial fibrosis in norm and in certain cardiovascular diseases, how to diagnose it. Russ Med Acad Contin post-graduate Stud 75–81. https://doi.org/10.21518/2079-701X-2017-12-75-81
Aharinejad S, Krenn K, Paulus P, Schäfer R, Zuckermann A, Grimm M, Abraham D (2005) Differential role of TGF-β 1/bFGF and ET-1 in graft fibrosis in heart failure patients. Am J Transplant 5:2185–2192. https://doi.org/10.1111/j.1600-6143.2005.01006.x
Pan X, Chen Z, Huang R, Yao Y, Ma G (2013) Transforming Growth Factor β1 Induces the Expression of Collagen Type I by DNA Methylation in Cardiac Fibroblasts. PLoS One 8:1–8. https://doi.org/10.1371/journal.pone.0060335
Murphy SP, Kakkar R, McCarthy CP, Januzzi JL (2020) Inflammation in Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol 75:1324–1340. https://doi.org/10.1016/j.jacc.2020.01.014
Тепляков АТ, Шилов СН, Попова АА, Березикова ЕН, Гракова ЕВ, Неупокоева МН, Копьева КВ, Ратушняк ЕТ, Степачев ЕИ (2020) Роль провоспалительных цитокинов в развитии антрациклин-индуцированной сердечной недостаточности. Клинические исследования 35:66–74. [Teplyakov AT, Shilov SN, Popova AA, Berezikova EN, Grakova EV, Neupokoeva MN, Kopeva KV, Ratushnyak ET, Stepachev EI (2020) The role of pro-inflammatory cytokines in the development of anthracycline-induced heart failure. Clinical Studies 35:66–74. (In Russ)]. https://doi.org/10.29001/2073-8552-2020-35-2-66-74
Zhao W, Wang X, Sun KH, Zhou L (2018) Α-Smooth Muscle Actin Is Not a Marker of Fibrogenic Cell Activity in Skeletal Muscle Fibrosis. PLoS One 13:1–16. https://doi.org/10.1371/journal.pone.0191031
Herrera J, Henke CA, Bitterman PB (2018) Extracellular matrix as a driver of progressive fibrosis. J Clin Invest 128:45–53. https://doi.org/10.1172/JCI93557
Базылев ВВ, Канаева ТВ (2020) Роль матриксных металлопротеиназ в ремоделировании миокарда. CardioСоматика 11:22–28. [Bazylev VV, Kanaeva TV (2020) The role of matrix metalloproteinases in myocardial remodeling. CardioSomatics 11:22–28. (In Russ)]. https://doi.org/10.26442/22217185.2020.3.200374
Ma ZG, Yuan YP, Wu HM, Zhang X, Tang QZ (2018) Cardiac fibrosis: New insights into the pathogenesis. Int J Biol Sci 14:1645–1657. https://doi.org/10.7150/ijbs.28103
Medeiros-Lima DJM, Carvalho JJ, Tibirica E, Borges JP, Matsuura C (2019) Time course of cardiomyopathy induced by doxorubicin in rats. Pharmacol Reports 71:583–590. https://doi.org/10.1016/j.pharep.2019.02.013
Lončar-Turukalo T, Vasić M, Tasić T, Mijatović G, Glumac S, Bajić D, Japunžić-Žigon N (2015) Heart rate dynamics in doxorubicin-induced cardiomyopathy. Physiol Meas 36:727–739. https://doi.org/10.1088/0967-3334/36/4/727
Merlet N, Piriou N, Rozec B, Grabherr A, Lauzier B, Trochu JN, Gauthier C (2013) Increased Beta2-Adrenoceptors in Doxorubicin-Induced Cardiomyopathy in Rat. PLoS One 8:1–15. https://doi.org/10.1371/journal.pone.0064711
Podyacheva EY, Kushnareva EA, Karpov AA, Toropova YG (2021) Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician. Front Pharmacol 12:1–12. https://doi.org/10.3389/fphar.2021.670479
Rolski F, Błyszczuk P (2020) Complexity of TNF-α signaling in heart disease. J Clin Med 9:1–25. https://doi.org/10.3390/jcm9103267
Sun M, Chen M, Dawood F, Zurawska U, Li JY, Parker T, Kassiri Z, Kirshenbaum LA, Arnold M, Khokha R, Liu PP (2007) Tumor necrosis factor-α mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation 115:1398–1407. https://doi.org/10.1161/CIRCULATIONAHA.106.643585
Shi-wen X, Kennedy L, Renzoni EA, Bou-Gharios G, Du Bois RM, Black CM, Denton CP, Abraham DJ, Leask A (2007) Endothelin is a downstream mediator of profibrotic responses to transforming growth factor β in human lung fibroblasts. Arthritis Rheum 56:4189–4194. https://doi.org/10.1002/art.23134
Podyacheva E, Toropova Y (2022) SIRT1 activation and its effect on intercalated disc proteins as a way to reduce doxorubicin cardiotoxicity. Front Pharmacol 13:1–23. https://doi.org/10.3389/fphar.2022.1035387
Сабиров ЛФ, Фролова ЭБ, Мухаметшина, Г.А. Сафаргалиева, Л.Х. Мухитова ЭИ (2012) Диллатационная кардиомипатия. Клинический случай 5:202–208. [Sabirov LF, Frolova EB, Mukhametshina GA, Safargalieva LKh, Mukhitova EI (2012) Dilated cardiomyopathy. Clinical Case 5:202–208. (In Russ)]. https://doi.org/10.1016/B978-0-323-47870-0.00022-2
Ahmedova DM, Hojakuliyev BG (2014) Value of Volume Fraction of Collagen in Development of Myocardium Remodeling At the Patients With Inflammatory Cardiomyopathy. Eurasian Hear J 109–112. https://doi.org/10.38109/2225-1685-2014-1-109-112
Найдич АМ (2006) Структурная неоднородность левого желудочка и ремоделирование миокарда. Бюллетень сибирской медицины 5:38–45. [Naiditsch AM (2006) Left ventricular structural heterogeneity and myocardial remodelling. Bulletin of Siberian Medicine 5:38–45. (In Russ)]. https://doi.org/10.20538/1682-0363-2006-1-38-45
Shishkova AV, Adonina EV, Duplyakov DV, Suslina EA, Ksenofontova LV (2018) Course and outcome of dilated cardiomyopathy. Cardiol News, Opin Training 6:92–96. https://doi.org/10.24411/2309-1908-2018-13010
Schiller M, Javelaud D, Mauviel A (2004) TGF-β-induced SMAD signaling and gene regulation: Consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci 35:83–92. https://doi.org/10.1016/j.jdermsci.2003.12.006
Hafizi S, Wharton J, Chester AH, Yacoub MH (2004) Profibrotic effects of endothelin-1 via the ET A receptor in cultured human cardiac fibroblasts. Cell Physiol Biochem 14:285–292. https://doi.org/10.1159/000080338
Neri Serneri GG, Cecioni I, Vanni S, Paniccia R, Bandinelli B, Vetere A, Janming X, Bertolozzi I, Boddi M, Lisi GF, Sani G, Modesti PA (2000) Selective upregulation of cardiac endothelin system in patients with ischemic but not idiopathic dilated cardiomyopathy: Endothelin-1 system in the human failing heart. Circ Res 86:377–385. https://doi.org/10.1161/01.res.86.4.377
Remuzzi G, Perico N, Benigni A (2002) New therapeutics that antagonize endothelin: Promises and frustrations. Nat Rev Drug Discov 1:986–1001. https://doi.org/10.1038/nrd962
Tanaka R, Umemura M, Narikawa M, Hikichi M, Osaw K, Fujita T, Yokoyama U, Ishigami T, Tamura K, Ishikawa Y (2020) Reactive fibrosis precedes doxorubicin-induced heart failure through sterile inflammation. ESC Hear Fail 7:588–603. https://doi.org/10.1002/ehf2.12616
Sun KH, Chang Y, Reed NI, Sheppard D (2016) α-smooth muscle actin is an inconsistent marker of fibroblasts responsible for force-dependent TGFβ activation or collagen production across multiple models of organ fibrosis. Am J Physiol - Lung Cell Mol Physiol 310:L824–L836. https://doi.org/10.1152/ajplung.00350.2015