clinmedКлиническая медицинаClinical Medicine (Russian Journal)0023-21492412-1339ООО «Медицинское информационное агентство»10.30629/0023-2149-2023-101-1-18-25clinmed-495Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEWS AND LECTURESПромышленные поллютанты и эпигенетические факторы, ассоциированные с кардиомиопатиямиIndustrial pollutans and epigenetic factors associated with cardiomyopathieshttps://orcid.org/0000-0003-0071-4866НечаевД. Н.NechaevD. N.

Нечаев Денис Николаевич — ведущий аналитик

119121, Москва

Nechaev Denis N.

119121, Moscow

https://orcid.org/0000-0002-9564-9755МиролюбовА. А.MirolyubovA. A.

Миролюбов Александр Александрович — аналитик

119121, Москва

Mirolyubov Alexander A.

119121, Moscow

https://orcid.org/0000-0002-6716-0266МилоголоваД. С.MilogolovaD. S.

Милоголова Дарья Сергеевна — аналитик

119121, Москва

Milogolova Daria S.

119121, Moscow

dmilogolova@cspfmba.ruhttps://orcid.org/0000-0001-8018-4775ПопругаК. Э.PoprugaK. E.

Попруга Катерина Эдуардовна — аналитик 2-й категории

119121, Москва

Popruga Katerina E.

119121, Moscow

https://orcid.org/0000-0003-1822-9842ТитоваА. Г.TitovaA. G.

Титова Анастасия Германовна — аналитик 2-й категории

119121, Москва

Titova Anastasia G.

119121, Moscow

https://orcid.org/0000-0003-2036-3514ЛомовА. Н.LomovA. N.

Ломов Алексей Николаевич  — начальник отдела

119121, Москва

Lomov Alexey N.

119121, Moscow

ФГБУ «Центр стратегического планирования и управления медико-биологическими рисками здоровью» Федерального медико-биологического агентстваРоссияCentre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological AgencyRussian Federation20232603202310111825Copyright © Нечаев Д.Н., Миролюбов А.А., Милоголова Д.С., Попруга К.Э., Титова А.Г., Ломов А.Н., 20232023Нечаев Д.Н., Миролюбов А.А., Милоголова Д.С., Попруга К.Э., Титова А.Г., Ломов А.Н.Nechaev D.N., Mirolyubov A.A., Milogolova D.S., Popruga K.E., Titova A.G., Lomov A.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.clinmedjournal.com/jour/article/view/495

В статье представлен обзор современных научных публикаций, посвященных отдельным аспектам молекулярно-генетического и эпигенетического патогенеза некоторых видов кардиомиопатий и представляющих интерес в том числе с точки зрения возможных ассоциаций с патофизиологическими механизмами воздействия поллютантов и промышленных ядов. Актуальность обозначенного подхода связана с тем, что указанные токсические агенты в настоящее время признаются рядом авторов как один из основных факторов, способствующих развитию сердечно- сосудистых заболеваний, и потребность в разносторонней теоретической базе для потенциальной разработки соответствующих средств профилактики и фармакологической коррекции становится все более и более осознанной. В фокусе повествования находятся функциональные цепи mTOR, фактора трансляции eIF4E и сплайсинг-регулятора RBM20, замыкающиеся на подверженные действию поллютантов регуляторные каскады ренин-ангиотензин-альдостероновой системы и гормональной системы трийодтиронина (Т3). Отдельное внимание уделено вопросам связи изменений профиля метилирования генома кардиомиоцитов с токсикодинамикой поллютантов и патогенезом кардиомиопатий.

The article presents a review of current scientific articles related to a few particular questions of molecular-genetic and epigenetic pathogenesis of some cardiomyopathy types that can be the object of interest assuming potential associations with pathophysiological mechanisms of pollutants and industrial toxins impaction. The possible benefits may arise from that kind of approach due to the fact that toxic agents in question are generally recognized at the moment as one of the cardiovascular disease onset and progression factors. The need for multidirectional theoretical developments targeting potential pharmacology methods aimed to at least partially eliminate such a challenge becomes more and more apparent. We focused on mTOR function chains, translation factor eIF4E and splicing regulator RBM20 interconnected with RAAS and T3 regulatory cascades. A part of our attention was also concentrated on cardiomyocytes methylome profiling in connection with pollutant toxicodynamics and cardiomyopathies pathogenesis.

дилатационная кардиомиопатиягипертрофическая кардиомиопатиягипертрофия миокардаполлютантымишень рапамицинаmTOReIF4Eтитинметилирование ДНКRBM20dilated cardiomyopathyhypertrophic cardiomyopathycardiac hypertrophypollutantstarget of rapamycinmTOReIF4EtitinDNA methylationRBM20ReferencesChahwan R., Wontakal S.N., Roa S. The multidimensional nature of epigenetic information and its role in disease. Discov Med. 2011;11(58):233–43. PMID: 21447282Chahwan R., Wontakal S.N., Roa S. The multidimensional nature of epigenetic information and its role in disease. Discov Med. 2011;11(58):233–43. PMID: 21447282Sun Q., Ren X., Sun Z., Duan J. The critical role of epigenetic mechanism in PM2.5-induced cardiovascular diseases. Genes. Environ. 2021;43(1):47. DOI: 10.1186/s41021-021-00219-wSun Q., Ren X., Sun Z., Duan J. The critical role of epigenetic mechanism in PM2.5-induced cardiovascular diseases. Genes. Environ. 2021;43(1):47. DOI: 10.1186/s41021-021-00219-wKonduracka E., Rostoff P. Links between chronic exposure to outdoor air pollution and cardiovascular diseases: a review. Environ. Chem. Lett. (2022). DOI: 10.1007/s10311-022-01450-9Konduracka E., Rostoff P. Links between chronic exposure to outdoor air pollution and cardiovascular diseases: a review. Environ. Chem. Lett. (2022). DOI: 10.1007/s10311-022-01450-9Cox E.J., Marsh S.A. A systematic review of fetal genes as biomarkers of cardiac hypertrophy in rodent models of diabetes. PLoS One. 2014;9(3):e92903. DOI: 10.1371/journal.pone.0092903Cox E.J., Marsh S.A. A systematic review of fetal genes as biomarkers of cardiac hypertrophy in rodent models of diabetes. PLoS One. 2014;9(3):e92903. DOI: 10.1371/journal.pone.0092903Taegtmeyer H., Sen S., Vela D. Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann. N.-Y. Acad. Sci. 2010;1188:191–8. DOI: 10.1111/j.1749-6632.2009.05100.xTaegtmeyer H., Sen S., Vela D. Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann. N.-Y. Acad. Sci. 2010;1188:191–8. DOI: 10.1111/j.1749-6632.2009.05100.xZeitz M.J., Smyth J.W. Translating Translation to Mechanisms of Cardiac Hypertrophy. J. Cardiovasc. Dev. Dis. 2020;7(1):9. DOI: 10.3390/jcdd7010009Zeitz M.J., Smyth J.W. Translating Translation to Mechanisms of Cardiac Hypertrophy. J. Cardiovasc. Dev. Dis. 2020;7(1):9. DOI: 10.3390/jcdd7010009Perrino C., Naga Prasad S.V., Mao L., Noma T., Yan Z., Kim H.S., Smithies O., Rockman H.A. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J. Clin. Invest. 2006;116(6):1547–60. DOI: 10.1172/JCI25397Perrino C., Naga Prasad S.V., Mao L., Noma T., Yan Z., Kim H.S., Smithies O., Rockman H.A. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J. Clin. Invest. 2006;116(6):1547–60. DOI: 10.1172/JCI25397Burke M.A., Chang S., Wakimoto H., Gorham J.M., Conner D.A., Christodoulou D.C., Parfenov M.G., DePalma S.R., Eminaga S., Konno T., Seidman J.G., Seidman C.E. Molecular profi ling of dilated cardiomyopathy that progresses to heart failure. JCI Insight. 2016;1(6):e86898. DOI: 10.1172/jci.insight.86898Burke M.A., Chang S., Wakimoto H., Gorham J.M., Conner D.A., Christodoulou D.C., Parfenov M.G., DePalma S.R., Eminaga S., Konno T., Seidman J.G., Seidman C.E. Molecular profi ling of dilated cardiomyopathy that progresses to heart failure. JCI Insight. 2016;1(6):e86898. DOI: 10.1172/jci.insight.86898Hannan R.D., Jenkins A., Jenkins A.K., Brandenburger Y. Cardiac hypertrophy: a matter of translation. Clin. Exp. Pharmacol. Physiol. 2003;30(8):517–27. DOI: 10.1046/j.1440-1681.2003.03873.xHannan R.D., Jenkins A., Jenkins A.K., Brandenburger Y. Cardiac hypertrophy: a matter of translation. Clin. Exp. Pharmacol. Physiol. 2003;30(8):517–27. DOI: 10.1046/j.1440-1681.2003.03873.xSchwanhäusser B., Busse D., Li N., Dittmar G., Schuchhardt J., Wolf J., Chen W., Selbach M. Global quantifi cation of mammalian gene expression control. Nature. 2011;473(7347):337–42. DOI: 10.1038/nature10098. Erratume in Nature. 2013;495(7439):126–7. PMID: 21593866Schwanhäusser B., Busse D., Li N., Dittmar G., Schuchhardt J., Wolf J., Chen W., Selbach M. Global quantifi cation of mammalian gene expression control. Nature. 2011;473(7347):337–42. DOI: 10.1038/nature10098. Erratume in Nature. 2013;495(7439):126–7. PMID: 21593866Spruill L.S., Baicu C.F., Zile M.R., McDermott P.J. Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload. J. Mol. Cell. Cardiol. 2008;44(1):69–75. DOI: 10.1016/j.yjmcc.2007.10.011Spruill L.S., Baicu C.F., Zile M.R., McDermott P.J. Selective translation of mRNAs in the left ventricular myocardium of the mouse in response to acute pressure overload. J. Mol. Cell. Cardiol. 2008;44(1):69–75. DOI: 10.1016/j.yjmcc.2007.10.011Amorim I.S., Lach G., Gkogkas C.G. The Role of the Eukaryotic Translation Initiation Factor 4E (eIF4E) in Neuropsychiatric Disorders. Front Genet. 2018;9:561. DOI: 10.3389/fgene.2018.00561Amorim I.S., Lach G., Gkogkas C.G. The Role of the Eukaryotic Translation Initiation Factor 4E (eIF4E) in Neuropsychiatric Disorders. Front Genet. 2018;9:561. DOI: 10.3389/fgene.2018.00561Romagnoli A., D'Agostino M., Ardiccioni C., Maracci C., Motta S., La Teana A., Di Marino D. Control of the eIF4E activity: structural insights and pharmacological implications. Cell Mol. Life Sci. 2021;78(21–22):6869–6885. DOI: 10.1007/s00018-021-03938-zRomagnoli A., D'Agostino M., Ardiccioni C., Maracci C., Motta S., La Teana A., Di Marino D. Control of the eIF4E activity: structural insights and pharmacological implications. Cell Mol. Life Sci. 2021;78(21–22):6869–6885. DOI: 10.1007/s00018-021-03938-zHinnebusch A.G., Ivanov I.P., Sonenberg N. Translational control by 5'-untranslated regions of eukaryotic mRNAs. Science. 2016;352(6292):1413–6. DOI: 10.1126/science.aad9868Hinnebusch A.G., Ivanov I.P., Sonenberg N. Translational control by 5'-untranslated regions of eukaryotic mRNAs. Science. 2016;352(6292):1413–6. DOI: 10.1126/science.aad9868Truitt M.L., Conn C.S., Shi Z., Pang X., Tokuyasu T., Coady A.M., Seo Y., Barna M., Ruggero D. Diff erential Requirements for eIF4E Dose in Normal Development and Cancer. Cell. 2015;162(1):59–71. DOI: 10.1016/j.cell.2015.05.049Truitt M.L., Conn C.S., Shi Z., Pang X., Tokuyasu T., Coady A.M., Seo Y., Barna M., Ruggero D. Diff erential Requirements for eIF4E Dose in Normal Development and Cancer. Cell. 2015;162(1):59–71. DOI: 10.1016/j.cell.2015.05.049Truitt M.L., Conn C.S., Shi Z., Pang X., Tokuyasu T., Coady A.M., Seo Y., Barna M., Ruggero D. Diff erential Requirements for eIF4E Dose in Normal Development and Cancer. Cell. 2015;162(1):59–71. DOI: 10.1016/j.cell.2015.05.049Truitt M.L., Conn C.S., Shi Z., Pang X., Tokuyasu T., Coady A.M., Seo Y., Barna M., Ruggero D. Diff erential Requirements for eIF4E Dose in Normal Development and Cancer. Cell. 2015;162(1):59–71. DOI: 10.1016/j.cell.2015.05.049Korneeva N.L., Song A., Gram H., Edens M.A., Rhoads R.E. Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Aff ects Translation of mRNAs Containing Both a 5'-Terminal Cap and Hairpin. J. Biol. Chem. 2016;291(7):3455–67. DOI: 10.1074/jbc.M115.694190Korneeva N.L., Song A., Gram H., Edens M.A., Rhoads R.E. Inhibition of Mitogen-activated Protein Kinase (MAPK)-interacting Kinase (MNK) Preferentially Aff ects Translation of mRNAs Containing Both a 5'-Terminal Cap and Hairpin. J. Biol. Chem. 2016;291(7):3455–67. DOI: 10.1074/jbc.M115.694190Fan C., Iacobas D.A., Zhou D., Chen Q., Lai J.K., Gavrialov O., Haddad G.G. Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia. Physiol. Genom. 2005;22:292–307.Fan C., Iacobas D.A., Zhou D., Chen Q., Lai J.K., Gavrialov O., Haddad G.G. Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia. Physiol. Genom. 2005;22:292–307.Nagatomo Y., Carabello B.A., Hamawaki M., Nemoto S., Matsuo T., McDermott P.J. Translational mechanisms accelerate the rate of protein synthesis during canine pressure-overload hypertrophy. Am. J. Physiol. Content. 1999;277:H2176–H2184.Nagatomo Y., Carabello B.A., Hamawaki M., Nemoto S., Matsuo T., McDermott P.J. Translational mechanisms accelerate the rate of protein synthesis during canine pressure-overload hypertrophy. Am. J. Physiol. Content. 1999;277:H2176–H2184.Holz M.K., Ballif B.A., Gygi S.P., Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123(4):569–80. DOI: 10.1016/j.cell.2005.10.024Holz M.K., Ballif B.A., Gygi S.P., Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123(4):569–80. DOI: 10.1016/j.cell.2005.10.024Chauvin C., Koka V., Nouschi A., Mieulet V., Hoareau-Aveilla C., Dreazen A., Cagnard N., Carpentier W., Kiss T., Meyuhas O., Pende M. Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene. 2014;33(4):474–83. DOI: 10.1038/onc.2012.606Chauvin C., Koka V., Nouschi A., Mieulet V., Hoareau-Aveilla C., Dreazen A., Cagnard N., Carpentier W., Kiss T., Meyuhas O., Pende M. Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene. 2014;33(4):474–83. DOI: 10.1038/onc.2012.606Zhang D., Contu R., Latronico M.V., Zhang J., Rizzi R., Catalucci D., Miyamoto S., Huang K., Ceci M., Gu Y., Dalton N.D., Peterson K.L., Guan K.L., Brown J.H., Chen J., Sonenberg N., Condorelli G. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J. Clin. Invest. 2010;120(8):2805–16. DOI: 10.1172/JCI43008. Erratum in J. Clin. Invest. 2010;120(10):3735. Zhang, Jian Ling [corrected to Zhang, Jianlin]. 1Zhang D., Contu R., Latronico M.V., Zhang J., Rizzi R., Catalucci D., Miyamoto S., Huang K., Ceci M., Gu Y., Dalton N.D., Peterson K.L., Guan K.L., Brown J.H., Chen J., Sonenberg N., Condorelli G. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J. Clin. Invest. 2010;120(8):2805–16. DOI: 10.1172/JCI43008. Erratum in J. Clin. Invest. 2010;120(10):3735. Zhang, Jian Ling [corrected to Zhang, Jianlin]. 1Zhu Y., Pires K.M., Whitehead K.J., Olsen C.D., Wayment B., Zhang Y.C., Bugger H., Ilkun O., Litwin S.E., Thomas G., Kozma S.C., Abel E.D. Mechanistic target of rapamycin (Mtor) is essential for murine embryonic heart development and growth. PLoS One. 2013;8(1):e54221. DOI: 10.1371/journal.pone.0054221Zhu Y., Pires K.M., Whitehead K.J., Olsen C.D., Wayment B., Zhang Y.C., Bugger H., Ilkun O., Litwin S.E., Thomas G., Kozma S.C., Abel E.D. Mechanistic target of rapamycin (Mtor) is essential for murine embryonic heart development and growth. PLoS One. 2013;8(1):e54221. DOI: 10.1371/journal.pone.0054221Mazelin L., Panthu B., Nicot A.S., Belotti E., Tintignac L., Teixeira G., Zhang Q., Risson V., Baas D., Delaune E., Derumeaux G., Taillandier D., Ohlmann T., Ovize M., Gangloff Y.G., Schaeff er L. mTOR inactivation in myocardium from infant mice rapidly leads to dilated cardiomyopathy due to translation defects and p53/JNK-mediated apoptosis. J. Mol. Cell Cardiol. 2016;97:213–25. DOI: 10.1016/j.yjmcc.2016.04.011Mazelin L., Panthu B., Nicot A.S., Belotti E., Tintignac L., Teixeira G., Zhang Q., Risson V., Baas D., Delaune E., Derumeaux G., Taillandier D., Ohlmann T., Ovize M., Gangloff Y.G., Schaeff er L. mTOR inactivation in myocardium from infant mice rapidly leads to dilated cardiomyopathy due to translation defects and p53/JNK-mediated apoptosis. J. Mol. Cell Cardiol. 2016;97:213–25. DOI: 10.1016/j.yjmcc.2016.04.011Shende P., Plaisance I., Morandi C., Pellieux C., Berthonneche C., Zorzato F., Krishnan J., Lerch R., Hall M.N., Rüegg M.A., Pedrazzini T., Brink M. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation. 2011;123(10):1073–82. DOI: 10.1161/CIRCULATIONAHA.110.977066Shende P., Plaisance I., Morandi C., Pellieux C., Berthonneche C., Zorzato F., Krishnan J., Lerch R., Hall M.N., Rüegg M.A., Pedrazzini T., Brink M. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation. 2011;123(10):1073–82. DOI: 10.1161/CIRCULATIONAHA.110.977066McMullen J.R., Sherwood M.C., Tarnavski O., Zhang L., Dorfman A.L., Shioi T., Izumo S. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation. 2004;109(24):3050–5. DOI: 10.1161/01.CIR.0000130641.08705.45McMullen J.R., Sherwood M.C., Tarnavski O., Zhang L., Dorfman A.L., Shioi T., Izumo S. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation. 2004;109(24):3050–5. DOI: 10.1161/01.CIR.0000130641.08705.45Völkers M., Toko H., Doroudgar S., Din S., Quijada P., Joyo A.Y., Ornelas L., Joyo E., Thuerauf D.J., Konstandin M.H., Gude N., Glembotski C.C., Sussman M.A. Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1. Proc. Natl. Acad. Sci. USA. 2013;110(31):12661–6. DOI: 10.1073/pnas.1301455110Völkers M., Toko H., Doroudgar S., Din S., Quijada P., Joyo A.Y., Ornelas L., Joyo E., Thuerauf D.J., Konstandin M.H., Gude N., Glembotski C.C., Sussman M.A. Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1. Proc. Natl. Acad. Sci. USA. 2013;110(31):12661–6. DOI: 10.1073/pnas.1301455110Ranek M.J., Kokkonen-Simon K.M., Chen A., Dunkerly-Eyring B.L., Vera M.P., Oeing C.U., Patel C.H., Nakamura T., Zhu G., Bedja D., Sasaki M., Holewinski R.J., Van Eyk J.E., Powell J.D., Lee D.I., Kass D.A. PKG1-modifi ed TSC2 regulates mTORC1 activity to counter adverse cardiac stress. Nature. 2019;566(7743):264–269. DOI: 10.1038/s41586-019-0895-yRanek M.J., Kokkonen-Simon K.M., Chen A., Dunkerly-Eyring B.L., Vera M.P., Oeing C.U., Patel C.H., Nakamura T., Zhu G., Bedja D., Sasaki M., Holewinski R.J., Van Eyk J.E., Powell J.D., Lee D.I., Kass D.A. PKG1-modifi ed TSC2 regulates mTORC1 activity to counter adverse cardiac stress. Nature. 2019;566(7743):264–269. DOI: 10.1038/s41586-019-0895-yGonzález-Terán B., López J.A., Rodríguez E., Leiva L., Martínez-Martínez S., Bernal J.A., Jiménez-Borreguero L.J., Redondo J.M., Vazquez J., Sabio G. p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation. Nat. Commun. 2016;7:10477. DOI: 10.1038/ncomms10477González-Terán B., López J.A., Rodríguez E., Leiva L., Martínez-Martínez S., Bernal J.A., Jiménez-Borreguero L.J., Redondo J.M., Vazquez J., Sabio G. p38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation. Nat. Commun. 2016;7:10477. DOI: 10.1038/ncomms10477Li Z., Carter JD., Dailey L.A., Huang Y.C. Pollutant particles produce vasoconstriction and enhance MAPK signaling via angiotensin type I receptor. Environ. Health Perspect. 2005;113(8):1009–14. DOI: 10.1289/ehp.7736. PMID: 16079071; PMCID: PMC1280341Li Z., Carter JD., Dailey L.A., Huang Y.C. Pollutant particles produce vasoconstriction and enhance MAPK signaling via angiotensin type I receptor. Environ. Health Perspect. 2005;113(8):1009–14. DOI: 10.1289/ehp.7736. PMID: 16079071; PMCID: PMC1280341Giorgini P., Di Giosia P., Grassi D., Rubenfi re M., Brook R.D., Ferri C. Air Pollution Exposure and Blood Pressure: An Updated Review of the Literature. Curr. Pharm. Des. 2016;22(1):28–51. DOI: 10.2174/1381612822666151109111712Giorgini P., Di Giosia P., Grassi D., Rubenfi re M., Brook R.D., Ferri C. Air Pollution Exposure and Blood Pressure: An Updated Review of the Literature. Curr. Pharm. Des. 2016;22(1):28–51. DOI: 10.2174/1381612822666151109111712Sun C.Y., Chang S.C., Wu M.S. Uremic toxins induce kidney fi - brosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition. PLoS One. 2012;7(3):e34026. DOI: 10.1371/journal.pone.0034026Sun C.Y., Chang S.C., Wu M.S. Uremic toxins induce kidney fi - brosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition. PLoS One. 2012;7(3):e34026. DOI: 10.1371/journal.pone.0034026Zhang J.-x., Zhang Y.-p., Wu Q.-n. et al. Uric acid induces oxidative stress via an activation of the renin–angiotensin system in 3T3-L1 adipocytes. Endocrine. 2015;48:135–142. DOI: 10.1007/s12020-014-0239-5Zhang J.-x., Zhang Y.-p., Wu Q.-n. et al. Uric acid induces oxidative stress via an activation of the renin–angiotensin system in 3T3-L1 adipocytes. Endocrine. 2015;48:135–142. DOI: 10.1007/s12020-014-0239-5Chaudhary K., Malhotra K., Sowers J., Aroor A. Uric Acid — key ingredient in the recipe for cardiorenal metabolic syndrome. Cardiorenal Med. 2013;3(3):208–220. DOI: 10.1159/000355405Chaudhary K., Malhotra K., Sowers J., Aroor A. Uric Acid — key ingredient in the recipe for cardiorenal metabolic syndrome. Cardiorenal Med. 2013;3(3):208–220. DOI: 10.1159/000355405Afsar B., Elsurer Afsar R., Kanbay A., Covic A., Ortiz A., Kanbay M. Air pollution and kidney disease: review of current evidence. Clin. Kidney J. 2019;12(1):19–32. DOI: 10.1093/ckj/sfy111Afsar B., Elsurer Afsar R., Kanbay A., Covic A., Ortiz A., Kanbay M. Air pollution and kidney disease: review of current evidence. Clin. Kidney J. 2019;12(1):19–32. DOI: 10.1093/ckj/sfy111Yu T., Huang Z., Pu Z. Identifi cation of Potential Diagnostic Biomarkers and Biological Pathways in Hypertrophic Cardiomyopathy Based on Bioinformatics Analysis. Genes (Basel). 2022;13(3):530. DOI: 10.3390/genes13030530Yu T., Huang Z., Pu Z. Identifi cation of Potential Diagnostic Biomarkers and Biological Pathways in Hypertrophic Cardiomyopathy Based on Bioinformatics Analysis. Genes (Basel). 2022;13(3):530. DOI: 10.3390/genes13030530Herman DS., Lam L., Taylor M.R., Wang L., Teekakirikul P., Christodoulou D., Conner L., DePalma S.R., McDonough B., Sparks E., Teodorescu D.L., Cirino A.L., Banner N.R., Pennell D.J., Graw S., Merlo M., Di Lenarda A., Sinagra G., Bos J.M., Ackerman M.J., Mitchell R.N., Murry C.E., Lakdawala N.K., Ho C.Y., Barton P.J., Cook S.A., Mestroni L., Seidman J.G., Seidman C.E. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 2012;366(7):619–28. DOI: 10.1056/NEJMoa1110186Herman DS., Lam L., Taylor M.R., Wang L., Teekakirikul P., Christodoulou D., Conner L., DePalma S.R., McDonough B., Sparks E., Teodorescu D.L., Cirino A.L., Banner N.R., Pennell D.J., Graw S., Merlo M., Di Lenarda A., Sinagra G., Bos J.M., Ackerman M.J., Mitchell R.N., Murry C.E., Lakdawala N.K., Ho C.Y., Barton P.J., Cook S.A., Mestroni L., Seidman J.G., Seidman C.E. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 2012;366(7):619–28. DOI: 10.1056/NEJMoa1110186Guo W., Schafer S., Greaser M.L., Radke M.H., Liss M., Govindarajan T., Maatz H., Schulz H., Li S., Parrish A.M., Dauksaite V., Vakeel P., Klaassen S., Gerull B., Thierfelder L., Regitz-Zagrosek V., Hacker T.A., Saupe K.W., Dec G.W., Ellinor P.T., MacRae C.A., Spallek B., Fischer R., Perrot A., Özcelik C., Saar K., Hubner N., Gotthardt M. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat. Med. 2012;18(5):766–73. DOI: 10.1038/nm.2693Guo W., Schafer S., Greaser M.L., Radke M.H., Liss M., Govindarajan T., Maatz H., Schulz H., Li S., Parrish A.M., Dauksaite V., Vakeel P., Klaassen S., Gerull B., Thierfelder L., Regitz-Zagrosek V., Hacker T.A., Saupe K.W., Dec G.W., Ellinor P.T., MacRae C.A., Spallek B., Fischer R., Perrot A., Özcelik C., Saar K., Hubner N., Gotthardt M. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat. Med. 2012;18(5):766–73. DOI: 10.1038/nm.2693Larson E.J., Gregorich Z.R., Zhang Y., Li B.H., Aballo T.J., Melby J.A., Ge Y., Guo W. Rbm20 ablation is associated with changes in the expression of titin-interacting and metabolic proteins. Mol. Omics. 2022;18(7):627–634. DOI: 10.1039/d2mo00115bLarson E.J., Gregorich Z.R., Zhang Y., Li B.H., Aballo T.J., Melby J.A., Ge Y., Guo W. Rbm20 ablation is associated with changes in the expression of titin-interacting and metabolic proteins. Mol. Omics. 2022;18(7):627–634. DOI: 10.1039/d2mo00115bZhu C., Chen Z., Guo W. Pre-mRNA mis-splicing of sarcomeric genes in heart failure. Biochim. Biophys. Acta Mol. Basis Dis. 2017;1863(8):2056–2063. DOI: 10.1016/j.bbadis.2016.11.008Zhu C., Chen Z., Guo W. Pre-mRNA mis-splicing of sarcomeric genes in heart failure. Biochim. Biophys. Acta Mol. Basis Dis. 2017;1863(8):2056–2063. DOI: 10.1016/j.bbadis.2016.11.008Li S., Guo W., Dewey C.N., Greaser M.L. Rbm20 regulates titin alternative splicing as a splicing repressor. Nucleic Acids Res. 2013;41(4):2659–72. DOI: 10.1093/nar/gks1362Li S., Guo W., Dewey C.N., Greaser M.L. Rbm20 regulates titin alternative splicing as a splicing repressor. Nucleic Acids Res. 2013;41(4):2659–72. DOI: 10.1093/nar/gks1362Methawasin M., Hutchinson K.R., Lee E.J., Smith J.E. 3rd., Saripalli C., Hidalgo C.G., Ottenheijm C.A., Granzier H. Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a benefi cial eff ect on diastole. Circulation. 2014;129(19):1924–36. DOI: 10.1161/CIRCULATIONAHA.113.005610Methawasin M., Hutchinson K.R., Lee E.J., Smith J.E. 3rd., Saripalli C., Hidalgo C.G., Ottenheijm C.A., Granzier H. Experimentally increasing titin compliance in a novel mouse model attenuates the Frank-Starling mechanism but has a benefi cial eff ect on diastole. Circulation. 2014;129(19):1924–36. DOI: 10.1161/CIRCULATIONAHA.113.005610Li S., Guo W., Schmitt B.M., Greaser M.L. Comprehensive analysis of titin protein isoform and alternative splicing in normal and mutant rats. J. Cell Biochem. 2012;113(4):1265–73. DOI: 10.1002/jcb.23459Li S., Guo W., Schmitt B.M., Greaser M.L. Comprehensive analysis of titin protein isoform and alternative splicing in normal and mutant rats. J. Cell Biochem. 2012;113(4):1265–73. DOI: 10.1002/jcb.23459Greaser ML., Warren C.M., Esbona K., Guo W., Duan Y., Parrish A.M., Krzesinski P.R., Norman H.S., Dunning S., Fitzsimons D.P., Moss R.L. Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension. J .Mol. Cell Cardiol. 2008;44(6):983–91. DOI: 10.1016/j.yjmcc.2008.02.272Greaser ML., Warren C.M., Esbona K., Guo W., Duan Y., Parrish A.M., Krzesinski P.R., Norman H.S., Dunning S., Fitzsimons D.P., Moss R.L. Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension. J .Mol. Cell Cardiol. 2008;44(6):983–91. DOI: 10.1016/j.yjmcc.2008.02.272Guo W., Pleitner J.M., Saupe K.W., Greaser M.L. Pathophysiological defects and transcriptional profi ling in the RBM20-/- rat model. PLoS One. 2013;8(12):e84281. DOI: 10.1371/journal.pone.0084281Guo W., Pleitner J.M., Saupe K.W., Greaser M.L. Pathophysiological defects and transcriptional profi ling in the RBM20-/- rat model. PLoS One. 2013;8(12):e84281. DOI: 10.1371/journal.pone.0084281Streckfuss-Bömeke K., Tiburcy M., Fomin A., Luo X., Li W., Fischer C., Özcelik C., Perrot A., Sossalla S., Haas J., Vidal R.O., Rebs S., Khadjeh S., Meder B., Bonn S., Linke W.A., Zimmermann W.H., Hasenfuss G., Guan K. Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specifi c induced pluripotent stem cell-derived cardiomyocytes. J. Mol. Cell Cardiol. 2017;113:9–21. DOI: 10.1016/j.yjmcc.2017.09.008Streckfuss-Bömeke K., Tiburcy M., Fomin A., Luo X., Li W., Fischer C., Özcelik C., Perrot A., Sossalla S., Haas J., Vidal R.O., Rebs S., Khadjeh S., Meder B., Bonn S., Linke W.A., Zimmermann W.H., Hasenfuss G., Guan K. Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specifi c induced pluripotent stem cell-derived cardiomyocytes. J. Mol. Cell Cardiol. 2017;113:9–21. DOI: 10.1016/j.yjmcc.2017.09.008Briganti F., Sun H., Wei W., Wu J., Zhu C., Liss M., Karakikes I., Rego S., Cipriano A., Snyder M., Meder B., Xu Z., Millat G., Gotthardt M., Mercola M., Steinmetz L.M. iPSC Modeling of RBM20-Defi cient DCM Identifi es Upregulation of RBM20 as a Therapeutic Strategy. Cell Rep. 2020;32(10):108117. DOI: 10.1016/j.celrep.2020.108117Briganti F., Sun H., Wei W., Wu J., Zhu C., Liss M., Karakikes I., Rego S., Cipriano A., Snyder M., Meder B., Xu Z., Millat G., Gotthardt M., Mercola M., Steinmetz L.M. iPSC Modeling of RBM20-Defi cient DCM Identifi es Upregulation of RBM20 as a Therapeutic Strategy. Cell Rep. 2020;32(10):108117. DOI: 10.1016/j.celrep.2020.108117Maatz H., Jens M., Liss M., Schafer S., Heinig M., Kirchner M., Adami E., Rintisch C., Dauksaite V., Radke M.H., Selbach M., Barton P.J., Cook S.A., Rajewsky N., Gotthardt M., Landthaler M., Hubner N. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. J. Clin. Invest. 2014;124(8):3419–30. DOI: 10.1172/JCI74523Maatz H., Jens M., Liss M., Schafer S., Heinig M., Kirchner M., Adami E., Rintisch C., Dauksaite V., Radke M.H., Selbach M., Barton P.J., Cook S.A., Rajewsky N., Gotthardt M., Landthaler M., Hubner N. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. J. Clin. Invest. 2014;124(8):3419–30. DOI: 10.1172/JCI74523Zhu C., Yin Z., Ren J., McCormick R.J., Ford S.P., Guo W. RBM20 is an essential factor for thyroid hormone-regulated titin isoform transition. J. Mol. Cell Biol. 2015;7(1):88–90. DOI: 10.1093/jmcb/mjv002Zhu C., Yin Z., Ren J., McCormick R.J., Ford S.P., Guo W. RBM20 is an essential factor for thyroid hormone-regulated titin isoform transition. J. Mol. Cell Biol. 2015;7(1):88–90. DOI: 10.1093/jmcb/mjv002Steinmaus C.M. Perchlorate in Water Supplies: Sources, Exposures, and Health Eff ects. Curr. Environ. Health Rep. 2016;3(2):136–43. DOI: 10.1007/s40572-016-0087-ySteinmaus C.M. Perchlorate in Water Supplies: Sources, Exposures, and Health Eff ects. Curr. Environ. Health Rep. 2016;3(2):136–43. DOI: 10.1007/s40572-016-0087-yBraverman L.E., He X., Pino S., Cross M., Magnani B., Lamm S.H., Kruse M.B., Engel A., Crump K.S., Gibbs J.P. The eff ect of perchlorate, thiocyanate, and nitrate on thyroid function in workers exposed to perchlorate long-term. J. Clin. Endocrinol. Metab. 2005;90(2):700–6. DOI: 10.1210/jc.2004-1821Braverman L.E., He X., Pino S., Cross M., Magnani B., Lamm S.H., Kruse M.B., Engel A., Crump K.S., Gibbs J.P. The eff ect of perchlorate, thiocyanate, and nitrate on thyroid function in workers exposed to perchlorate long-term. J. Clin. Endocrinol. Metab. 2005;90(2):700–6. DOI: 10.1210/jc.2004-1821Kluska K., Adamczyk J., Krężel A. Metal binding properties of zinc fi ngers with a naturally altered metal binding site. Metallomics. 2018;10(2):248–263. DOI: 10.1039/c7mt00256dKluska K., Adamczyk J., Krężel A. Metal binding properties of zinc fi ngers with a naturally altered metal binding site. Metallomics. 2018;10(2):248–263. DOI: 10.1039/c7mt00256dHaas J., Frese K.S., Park Y.J., Keller A., Vogel B., Lindroth A.M., Weichenhan D., Franke J., Fischer S., Bauer A., Marquart S., Sedaghat-Hamedani F., Kayvanpour E., Köhler D., Wolf N.M., Hassel S., Nietsch R., Wieland T., Ehlermann P., Schultz J.H., Dösch A., Mereles D., Hardt S., Backs J., Hoheisel J.D., Plass C., Katus H.A., Me der B. Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mol. Med. 2013;5(3):413–29. DOI: 10.1002/emmm.201201553Haas J., Frese K.S., Park Y.J., Keller A., Vogel B., Lindroth A.M., Weichenhan D., Franke J., Fischer S., Bauer A., Marquart S., Sedaghat-Hamedani F., Kayvanpour E., Köhler D., Wolf N.M., Hassel S., Nietsch R., Wieland T., Ehlermann P., Schultz J.H., Dösch A., Mereles D., Hardt S., Backs J., Hoheisel J.D., Plass C., Katus H.A., Me der B. Alterations in cardiac DNA methylation in human dilated cardiomyopathy. EMBO Mol. Med. 2013;5(3):413–29. DOI: 10.1002/emmm.201201553Meder B., Haas J., Sedaghat-Hamedani F., Kayvanpour E., Frese K., Lai A., Nietsch R., Scheiner C., Mester S., Bordalo D.M., Amr A., Dietrich C., Pils D., Siede D., Hund H., Bauer A., Holzer D.B., Ruhparwar A., Mueller-Hennessen M., Weichenhan D., Plass C., Weis T., Backs J., Wuerstle M., Keller A., Katus H.A., Posch A.E. Epigenome-Wide Association Study Identifi es Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure. Circulation. 2017;136(16):1528–1544. DOI: 10.1161/CIRCULATIONAHA.117.027355Meder B., Haas J., Sedaghat-Hamedani F., Kayvanpour E., Frese K., Lai A., Nietsch R., Scheiner C., Mester S., Bordalo D.M., Amr A., Dietrich C., Pils D., Siede D., Hund H., Bauer A., Holzer D.B., Ruhparwar A., Mueller-Hennessen M., Weichenhan D., Plass C., Weis T., Backs J., Wuerstle M., Keller A., Katus H.A., Posch A.E. Epigenome-Wide Association Study Identifi es Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure. Circulation. 2017;136(16):1528–1544. DOI: 10.1161/CIRCULATIONAHA.117.027355Rider C.F., Carlsten C. Air pollution and DNA methylation: eff ects of exposure in humans. Clin. Epigenetics. 2019;11(1):131. DOI: 10.1186/s13148-019-0713-2Rider C.F., Carlsten C. Air pollution and DNA methylation: eff ects of exposure in humans. Clin. Epigenetics. 2019;11(1):131. DOI: 10.1186/s13148-019-0713-2

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