Эпигенетические лекарства: новый рубеж в лечении сердечной недостаточности
https://doi.org/10.38109/2225-1685-2023-4-76-82
Аннотация
Раскрытие секретов гибкости генома не только способствовало развитию исследований в этой области, но также послужило толчком к разработке новых методов лечения болезней человека. Лучшее понимание биологии хроматина (комплексы ДНК/гистоны) и некодирующих РНК (нкРНК) позволило разработать эпигенетические (эпи) препараты, способные модулировать программы транскрипции, связанные с сердечно-сосудистыми заболеваниями. Это особенно относится к сердечной недостаточности, где было показано, что эпигенетические механизмы лежат в основе развития некоторых патологических процессов, таких как гипертрофия левого желудочка, фиброз, апоптоз кардиомиоцитов и дисфункция микрососудов. Ориентация на эпигенетические сигналы может представлять собой многообещающий подход, особенно у пациентов с сердечной недостаточностью с сохраненной фракцией выброса (СНсФВ), где прогноз остается неблагоприятным, а эффективных методов лечения пока не существует. В этих условиях эпигенетика может использоваться для разработки индивидуальных терапевтических подходов, что прокладывает путь к персонализированной медицине. Несмотря на то, что благоприятные эффекты эпи-препаратов привлекают всё большее внимание, количество эпигенетических соединений, используемых в клинической практике, остается низким, что свидетельствует о необходимости разработки более селективных эпи-препаратов. В настоящем обзоре мы приводим перечень новых перспективных эпи-препаратов для лечения сердечно-сосудистых заболеваний, с акцентом, главным образом, на СНсФВ. Терапевтический эффект этих препаратов обусловлен воздействием как минимум на один из трёх основных эпигенетических механизмов: метилирование ДНК, модификация гистонов и некодирующие РНК.
Об авторах
К. А. АйтбаевКыргызстан
Кубаныч Авенович Айтбаев, д.м.н., профессор, заведующий отделением патологической физиологии, НИИ молекулярной биологии и медицины
ул. Тоголок молдо, дом 3, г. Бишкек 720040
И. Т. Муркамилов
Кыргызстан
Илхом Торобекович Муркамилов, д.м.н., доцент кафедры факультетской терапии
ул. И. Ахунбаева, 92, Бишкек 720020
ул. Киевская, 44, г. Бишкек 720000
Ж. А. Муркамилова
Кыргызстан
Жамила Абдилалимовна Муркамилова, аспирант
ул. Киевская, 44, г. Бишкек 720000
В. В. Фомин
Россия
Виктор Викторович Фомин, д.м.н., профессор, член-корр. РАН, Проректор по научно-исследовательской и клинической работе
ул. Трубецкая, д. 8, стр. 2, г. Москва
И. О. Кудайбергенова
Кыргызстан
Индира Орозобаевна Кудайбергенова, д.м.н., профессор, ректор
ул. И. Ахунбаева, 92, Бишкек 720020
Т. Ф. Юсупова
Кыргызстан
Турсуной Фуркатовна Юсупова, Студентка 5-го курса, медицинский факультет
ул. Ленина, 331, г. Ош 723500
Ф. А. Юсупов
Кыргызстан
Фуркат Абдулахатович Юсупов, д.м.н., профессор, зав каф. неврологии, нейрохирургии и психиатрии
ул. Ленина, 331, г. Ош 723500
Список литературы
1. Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006;114:A160–7. https://doi.org/10.1289/ehp.114-a160
2. Rozek LS, Dolinoy DC, Sartor MA, Omenn GS. Epigenetics: relevance and implications for public health. Annu Rev Public Health. 2014;35:105– 22. https://doi.org/10.1146/annurev-publhealth-032013-182513
3. Maunakea AK, Nagarajan RP, Bilenky M et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–7. https://doi.org/10.1038/nature09165
4. Mohammed SA, Ambrosini S, Lüscher T et al. Epigenetic control of mitochondrial function in the vasculature. Front Cardiovasc Med. 2020;7:28. https://doi.org/10.3389/fcvm.2020.00028
5. Handy DE, Castro R, Loscalzo J. Epigenetic modifications: basic mechanisms and role in cardiovascular disease. Circulation. 2011;123:2145–56. https://doi.org/10.1161/CIRCULATIONAHA.110.956839
6. Gao J, Shao K, Chen X et al. The involvement of post-translational modifications in cardiovascular pathologies: focus on SUMOylation, neddylation, succinylation, and prenylation. J Mol Cell Cardiol. 2020;138:49–58. https://doi.org/10.1016/j.yjmcc.2019.11.146
7. Das S, Shah R, Dimmeler S et al. Noncoding RNAs in cardiovascular disease: current knowledge, tools and technologies for investigation, and future directions: a scientific statement from the American heart association. Circ Genom Precis Med. 2020;13:e000062. https://doi.org/10.1161/HCG.0000000000000062
8. Zhong J, Agha G, Baccarelli AA. The role of DNA methylation in cardiovascular risk and disease. Circ Res. 2016;118:119–31. https://doi.org/10.1161/CIRCRESAHA.115.305206
9. Aggarwal R, Jha M, Shrivastava A, Jha AK. Natural compounds: role in reversal of epigenetic changes. Biochemistry. 2015;80:972–89. https://doi.org/10.1134/S0006297915080027
10. Ganesan A, Arimondo PB, Rots MG et al. The timeline of epigenetic drug discovery: from reality to dreams. Clin Epigenet. 2019;11:174. https://doi.org/10.1186/s13148-019-0776-0
11. Savarese G, Becher PM, Lund LH et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2023 Jan 18;118(17):3272-3287. https://doi.org/10.1093/cvr/cvac013
12. Redfield MM, Borlaug BA. Heart Failure With Preserved Ejection Fraction: A Review. JAMA. 2023 Mar 14;329(10):827-838. https://doi.org/10.1001/jama.2023.2020
13. Skinner MK. Role of epigenetics in developmental biology and transgenerational inheritance. Birth Defects Res C Embryo Today. 2011;93:51–5. https://doi.org/10.1002/bdrc.20199
14. From AM, Leibson CL, Bursi F et al. Diabetes in heart failure: prevalence and impact on outcome in the population. Am J Med. 2006;119:591–9. https://doi.org/10.1016/j.amjmed.2006.05.024
15. Liu CF, Tang WHW. Epigenetics in cardiac hypertrophy and heart failure. Basic Transl Sci. 2019;4:976–93. https://doi.org/10.1016/j.jacbts.2019.05.011
16. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;30:30–41. https://doi.org/10.1038/nrcardio.2010.165
17. Rich MW. Heart failure in the 21st century: a cardiogeriatric syndrome. J Gerontol A Biol Sci Med Sci. 2001;56:M88–96. https://doi.org/10.1093/gerona/56.2.M88
18. Backs J, Olson EN. Control of cardiac growth by histone acetylation/ deacetylation. Circ Res. 2006;98:15–24. https://doi.org/10.1161/01.RES.0000197782.21444.8f
19. Frey N, Katus HA, Olson EN, Hill JA. Hypertrophy of the heart: a new therapeutic target? Circulation. 2004; 109:1580–9. doi:10.1161/01.CIR.0000120390.68287.BB
20. Hill JA, Olson EN, Biology M-L. Mechanisms of disease cardiac plasticity. N Engl J Med. 2008;58:1370–80. https://doi.org/10.1056/NEJMra072139
21. Duygu B, de Windt LJ, da Costa Martins PA. Targeting microRNAs in heart failure. Trends Cardiovasc Med. 2016;26:99–110. https://doi.org/10.1016/j.tcm.2015.05.008
22. Ganesan A. Multitarget drugs: an epigenetic epiphany. ChemMedChem. 2016;11:1227–41. https://doi.org/10.1002/cmdc.201500394
23. Madsen A, Höppner G, Krause J et al. An important role for DNMT3amediated DNA methylation in cardiomyocyte metabolism and contractility. Circulation. 2020;142:1562–78. https://doi.org/10.1161/CIRCULATIONAHA.119.044444
24. Stenzig J, Schneeberger Y, Löser A et al. Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats. J Mol Cell Cardiol. 2018;120:53–63. https://doi.org/10.1016/j.yjmcc.2018.05.012
25. Gnyszka A, Jastrzebski Z, Flis S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 2013;33:2989–96.
26. Fraineau S, Palii CG, Allan DS, Brand M. Epigenetic regulation of endothelial-cell-mediated vascular repair. FEBS J. 2015;282:1605–29. https://doi.org/10.1111/febs.13183
27. Plácido R, Heinonen IHA, Volpe M et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol. 2018;10:1347. https://doi.org/10.3389/fphys.2019.01347
28. Rajan A, Shi H, Xue B. Class I and II histone deacetylase inhibitors differentially regulate thermogenic gene expression in brown adipocytes open. Sci Rep. 2018;8:13072. https://doi.org/10.1038/s41598-018-31560-w
29. Napoli C, Benincasa G, Donatelli F, Ambrosio G. Precision medicine in distinct heart failure phenotypes: focus on clinical epigenetics. Am Heart J. 2020;224:113–28. https://doi.org/10.1016/j.ahj.2020.03.007
30. Wang Y, Miao X, Liu Y et al. Dysregulation of histone acetyltransferases and deacetylases in cardiovascular diseases. Oxid Med Cell Longev. 2014;2014:641979. https://doi.org/10.1155/2014/641979
31. Kong Y, Tannous P, Lu G et al. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation. 2006;113:2579–88. https://doi.org/10.1161/CIRCULATIONAHA.106.625467
32. Granger A, Abdullah I, Huebner F et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J. 2008;22:3549–60. https://doi.org/10.1096/fj.08-108548
33. Xie M, Kong Y, Tan W et al. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation. 2014;129:1139–51. https://doi.org/10.1161/CIRCULATIONAHA.113.002416
34. Kee HJ, Sohn IS, Nam KI et al. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation. 2006 Jan 3;113(1):51-59. https://doi.org/10.1161/CIRCULATIONAHA.105.559724
35. Wallner M, Eaton DM, Berretta RM et al. HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction. Sci Transl Med. 2020;12:eaay7205. https://doi.org/10.1126/scitranslmed.aay7205
36. Testai L, Sestito S, Martelli A et al. Synthesis and pharmacological characterization of mitochondrial KATP channel openers with enhanced mitochondriotropic effects. Bioorgan Chem. 2021;107:104572. https://doi.org/10.1016/j.bioorg.2020.104572
37. Kelly WK, Marks P, Richon VM. CCR 20th anniversary commentary: vorinostat–gateway to epigenetic therapy. Clin Cancer Res. 2015;21:2198–200. https://doi.org/10.1158/1078-0432.CCR-14-2556
38. Ho TCS, Chan AHY, Ganesan A. Thirty years of HDAC inhibitors: 2020 insight and hindsight. J Med Chem Am Chem Soc. 2020;63:12460–84. https://doi.org/10.1021/acs.jmedchem.0c00830
39. Jeong MY, Lin YH, Wennersten SA et al. Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci Transl Med. 2018;10:eaao0144. https://doi.org/10.1126/scitranslmed.aao0144
40. Gillette T.G. HDAC inhibition in the heart: erasing hidden fibrosis. Circulation.2021;143(19):1891-1893. https://doi.org/10.1161/CIRCULATIONAHA.121.054262
41. Travers JG, Wennersten SA, Peña B, Bagchi RA, Smith HE, Hirsch RA, McKinsey TA. HDAC inhibition reverses preexisting diastolic dysfunction and blocks covert extracellular matrix remodeling. Circulation.2021;143(19):1874-1890. https://doi.org/10.1161/CIRCULATIONAHA.120.046462
42. Mattson RH, Cramer JA, Williamson PD, Novelly RA. Valproic acid in epilepsy: clinical and pharmacological effects. Ann Neurol. 1978;3:20– 5. https://doi.org/10.1002/ana.410030105
43. Mokhtarani M, Diaz GA, Rhead W et al. Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders. Mol Genet Metab. 2012;107:308–14. https://doi.org/10.1016/j.ymgme.2012.08.006
44. Tian S, Lei I, Gao W et al. HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction. EBioMedicine. 2019;39:83–94. https://doi.org/10.1016/j.ebiom.2018.12.003
45. Subramanian U, Kumar P, Mani I et al. Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice. Physiol Genomics. 2016;48:477–90. https://doi.org/10.1152/physiolgenomics.00073.2015
46. Chan-Penebre E, Kuplast KG, Majer CR et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015;11:432–7. https://doi.org/10.1038/nchembio.1810
47. Morera L, Lübbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenet. 2016;8:57. https://doi.org/10.1186/s13148-016-0223-4
48. Guo Y, Su Z-Y, Kong A-NT. Current perspectives on epigenetic modifications by dietary chemopreventive and herbal phytochemicals. Curr Pharmacol Rep. 2015;1:245–57. https://doi.org/10.1007/s40495-015-0023-0
49. Andrieu G, Belkina AC, Denis GV. Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol. 2016;19:45–50. https://doi.org/10.1016/j.ddtec.2016.06.004
50. Kalow W. Pharmacogenetics and pharmacogenomics: origin, status, and the hope for personalized medicine. Pharmacogenomics J. 2006;6:162–5. https://doi.org/10.1038/sj.tpj.6500361
51. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell Cell Press. 2014;54:728–36. https://doi.org/10.1016/j.molcel.2014.05.016
52. Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020;126:1190–208. https://doi.org/10.1161/CIRCRESAHA.120.315929
53. Nicholls SJ, Ray KK, Johansson JO et al. Selective BET protein inhibition with apabetalone and cardiovascular events: a pooled analysis of trials in patients with coronary artery disease. Am J Cardiovasc Drugs. 2018;18:109–15. https://doi.org/10.1007/s40256-017-0250-3
54. Nicholls SJ, Schwartz GG, Buhr KA et al. Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study. Cardiovasc Diabetol. 2021;20:13. https://doi.org/10.1186/s12933-020-01199-x
55. Tsujikawa LM, Fu L, Das S et al. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin Epigenet. 2019;11:102. https://doi.org/10.1186/s13148-019-0696-z
56. Brandts J, Ray KK. Apabetalone – BET protein inhibition in cardiovascular disease and type 2 diabetes. Future Cardiol. 2020;16:385–95. https://doi.org/10.2217/fca-2020-0017
57. Chioccioli M, Roy S, Rigby K et al. A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis. bioRxiv [Preprint]. 2021. https://doi.org/10.1101/2021.12.22.473724
58. van Rooij E, Sutherland LB, Thatcher JE et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci USA. 2008;105:13027–32. https://doi.org/10.1073/pnas.0805038105
59. Landmesser U, Poller W, Tsimikas S et al. From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur Heart J. 2020;41:3884–99. https://doi.org/10.1093/eurheartj/ehaa229
60. Gargiulo P, Marzano F, Salvatore M, et al. MicroRNAs: diagnostic, prognostic and therapeutic role in heart failure — a review. ESC Heart Failure. 2023;10:2:753-761. https://doi.org/10.1002/ehf2.14153
61. Ruan W, Zhao F, Zhao S et al. Knockdown of long noncoding RNA MEG3 impairs VEGF-stimulated endothelial sprouting angiogenesis via modulating VEGFR2 expression in human umbilical vein endothelial cells. Gene. 2018;649:32–9. https://doi.org/10.1016/j.gene.2018.01.072
62. Leisegang MS, Fork C, Josipovic I et al. Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation. 2017;136:65– 79. https://doi.org/10.1161/CIRCULATIONAHA.116.026991
63. Man HSJ, Sukumar AN, Lam GC et al. Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA. Proc Natl Acad Sci USA. 2018;115:2401–6. https://doi.org/10.1073/pnas.1715182115
64. Zhang X, Tang X, Hamblin MH, Yin K-J. Long non-coding RNA malat1 regulates angiogenesis in hindlimb ischemia. Int J Mol Sci. 2018; 19:1723. doi:10.3390/ijms19061723
65. Simion V, Haemmig S, Feinberg MW. LncRNAs in vascular biology and disease. Vasc Pharmacol. 2019;114:145–56. https://doi.org/10.1016/j.vph.2018.01.003
66. Miano JM, Zheng D, Bell RD et al. Identification and initial functional characterization of a human vascular cell-enriched long noncoding RNA. Arterioscler Thromb Vasc Biol. 2014;34:1249–59. https://doi.org/10.1161/ATVBAHA.114.303240
67. Vance KW, Schulte C, Thum T et al. Long non-coding RNAs: at the heart of cardiac dysfunction? Front Physiol. 2019;10:30. https://doi.org/10.3389/fphys.2019.00030
68. Zhou W, Wang C, Chang J et al. RNA methylations in cardiovascular diseases, molecular structure, biological functions and regulatory roles in cardiovascular diseases. Front Pharmacol. 2021;12:722728. https://doi.org/10.3389/fphar.2021.722728
69. Qin Y, Li L, Luo E et al. Role of m6A RNA methylation in cardiovascular disease (review). Int J Mol Med. 2020;46:1958–72. https://doi.org/10.3892/ijmm.2020.4746
70. Zhang B, Xu Y, Cui X et al. Alteration of m6A RNA methylation in heart failure with preserved ejection fraction. Front Cardiovasc Med. 2021;8:647806. https://doi.org/10.3389/fcvm.2021.647806
71. Cao M, Luo H, Li D et al. Research advances on circulating long noncoding RNAs as biomarkers of cardiovascular diseases. Int J Cardiol. 2022;353:109–17. https://doi.org/10.1016/j.ijcard.2022.01.070
Рецензия
Для цитирования:
Айтбаев К.А., Муркамилов И.Т., Муркамилова Ж.А., Фомин В.В., Кудайбергенова И.О., Юсупова Т.Ф., Юсупов Ф.А. Эпигенетические лекарства: новый рубеж в лечении сердечной недостаточности. Евразийский Кардиологический Журнал. 2023;(4):76-82. https://doi.org/10.38109/2225-1685-2023-4-76-82
For citation:
Aitbaev K.A., Murkamilov I.T., Murkamilova Zh.A., Fomin V.V., Kudaibergenova I.O., Yusupova T.F., Yusupov F.A. Epigenetic drugs: a new frontier in the treatment of heart failure. Eurasian heart journal. 2023;(4):76-82. (In Russ.) https://doi.org/10.38109/2225-1685-2023-4-76-82