Heart failure (HF) is the end stage of many cardiovascular diseases and seriously threatens people’s health. This article aimed to explore the biological role of fat-mass and obesity-associated gene (FTO) in HF. We constructed HF mouse model by transverse aortic constriction or intraperitoneal injection of doxorubicin. Mouse myocardial cells were exposed to hypoxia/reoxygenation (H/R). FTO and Mhrt were downregulated in heart tissues of HF mice. HF mice exhibited an increase in the total levels of N6 methyladenosine (m6A) and the m6A levels of Mhrt. Moreover, FTO overexpression caused an upregulation of Mhrt and reduced m6A modification of Mhrt in the H/R-treated myocardial cells. FTO upregulation repressed apoptosis of H/R-treated myocardial cells. FTO knockdown had the opposite results. Mhrt overexpression reduced apoptosis of H/R-treated myocardial cells. Moreover, the influence conferred by FTO upregulation was abolished by Mhrt knockdown. In conclusion, our data demonstrate that FTO overexpression inhibits apoptosis of hypoxia/reoxygenation-treated myocardial cells by regulating m6A modification of Mhrt. Thus, FTO may be a target gene for HF treatment.
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Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P (2018) Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 137:e67–e492. https://doi.org/10.1161/cir.0000000000000558
Duygu B, Poels EM, da Costa Martins PA (2013) Genetics and epigenetics of arrhythmia and heart failure. Front Genet 4:219. https://doi.org/10.3389/fgene.2013.00219
Aguilo F, Walsh MJ (2017) The N6-Methyladenosine RNA modification in pluripotency and reprogramming. Curr Opin Genet Dev 46:77–82. https://doi.org/10.1016/j.gde.2017.06.006
Coker H, Wei G, Brockdorff N (2019) m6A modification of non-coding RNA and the control of mammalian gene expression. Biochimica et biophysica acta Gene Regul Mech 1862:310–318. https://doi.org/10.1016/j.bbagrm.2018.12.002
Dorn LE, Lasman L, Chen J, Xu X, Hund TJ, Medvedovic M, Hanna JH, van Berlo JH, Accornero F (2019) The N-Methyladenosine mRNA Methylase METTL3 controls cardiac homeostasis and hypertrophy. Circulation 139:533–545. https://doi.org/10.1161/circulationaha.118.036146
Pan T (2013) N6-methyl-adenosine modification in messenger and long non-coding RNA. Trends Biochem Sci 38:204–209. https://doi.org/10.1016/j.tibs.2012.12.006
Gustavsson J, Mehlig K, Leander K, Lissner L, Bjorck L, Rosengren A, Nyberg F (2014) FTO genotype, physical activity, and coronary heart disease risk in Swedish men and women. Circ Cardiovasc Genet 7:171–177
Mathiyalagan P, Adamiak M, Mayourian J, Sassi Y, Liang Y, Agarwal N, Jha D, Zhang S, Kohlbrenner E, Chepurko E, Chen J, Trivieri MG, Singh R, Bouchareb R, Fish K, Ishikawa K, Lebeche D, Hajjar RJ, Sahoo S (2019) FTO-dependent N6-methyladenosine regulates cardiac function during remodeling and repair. Circulation 139:518–532. https://doi.org/10.1161/circulationaha.118.033794
Berulava T, Buchholz E, Elerdashvili V, Pena T, Islam MR, Lbik D, Mohamed BA, Renner A, von Lewinski D, Sacherer M, Bohnsack KE, Bohnsack MT, Jain G, Capece V, Cleve N, Burkhardt S, Hasenfuss G, Fischer A, Toischer K (2020) Changes in m6A RNA methylation contribute to heart failure progression by modulating translation. Eur J Heart Fail 22:54–66. https://doi.org/10.1002/ejhf.1672
Zhang L, Wu YJ, Zhang SL (2019) Circulating lncRNA MHRT predicts survival of patients with chronic heart failure. J Geriatric Cardiol JGC 16:818–821. https://doi.org/10.11909/j.issn.1671-5411.2019.11.006
Han P, Li W, Lin CH, Yang J, Shang C, Nuernberg ST, Jin KK, Xu W, Lin CY, Lin CJ, Xiong Y, Chien H, Zhou B, Ashley E, Bernstein D, Chen PS, Chen HV, Quertermous T, Chang CP (2014) A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514:102–106. https://doi.org/10.1038/nature13596
Li HQ, Wu YB, Yin CS, Chen L, Zhang Q, Hu LQ (2016) Obestatin attenuated doxorubicin-induced cardiomyopathy via enhancing long noncoding Mhrt RNA expression. Biomed Pharmacother 81:474–481. https://doi.org/10.1016/j.biopha.2016.04.017
Hampton C, Rosa R, Campbell B, Kennan R, Gichuru L, Ping X, Shen X, Small K, Madwed J, Lynch JJ (2017) Early echocardiographic predictors of outcomes in the mouse transverse aortic constriction heart failure model. J Pharmacol Toxicol Methods 84:93–101. https://doi.org/10.1016/j.vascn.2016.12.001
Karthiya R, Khandelia P (2020) m6A RNA methylation: ramifications for gene expression and human health. Mol Biotechnol. https://doi.org/10.1007/s12033-020-00269-5
Tuncel G, Kalkan R (2019) Importance of m N-methyladenosine (mA) RNA modification in cancer. Med Oncol 36:36. https://doi.org/10.1007/s12032-019-1260-6
Ferenc K, Pilžys T, Garbicz D, Marcinkowski M, Skorobogatov O, Dylewska M, Gajewski Z, Grzesiuk E, Zabielski R (2020) Intracellular and tissue specific expression of FTO protein in pig: changes with age, energy intake and metabolic status. Sci Rep 10:13029. https://doi.org/10.1038/s41598-020-69856-5
Hirayama M, Wei FY, Chujo T, Oki S, Yakita M, Kobayashi D, Araki N, Takahashi N, Yoshida R, Nakayama H, Tomizawa K (2020) FTO Demethylates cyclin D1 mRNA and controls cell-cycle progression. Cell Rep 31:107464. https://doi.org/10.1016/j.celrep.2020.03.028
Mathiyalagan P, Adamiak M, Mayourian J, Sassi Y, Liang Y, Agarwal N, Jha D, Zhang S, Kohlbrenner E, Chepurko E, Chen J, Trivieri MG, Singh R, Bouchareb R, Fish K, Ishikawa K, Lebeche D, Hajjar RJ, Sahoo S (2019) FTO-dependent N-Methyladenosine regulates cardiac function during remodeling and repair. Circulation 139:518–532. https://doi.org/10.1161/circulationaha.118.033794
Franczak A, Kolačkov K, Jawiarczyk-Przybyłowska A, Bolanowski M (2018) Association between FTO gene polymorphisms and HDL cholesterol concentration may cause higher risk of cardiovascular disease in patients with acromegaly. Pituitary 21:10–15. https://doi.org/10.1007/s11102-017-0840-8
Uchida S, Dimmeler S (2015) Long noncoding RNAs in cardiovascular diseases. Circ Res 116:737–750. https://doi.org/10.1161/circresaha.116.302521
Aboud HM, Mahmoud MO, Abdeltawab Mohammed M, Shafiq Awad M, Sabry D (2020) viaPreparation and appraisal of self-assembled valsartan-loaded amalgamated Pluronic F127/tween 80 polymeric micelles: boosted cardioprotection regulation of Mhrt/Nrf2 and Trx1 pathways in cisplatin-induced cardiotoxicity. J Drug Target 28:282–299. https://doi.org/10.1080/1061186x.2019.1650053
Zhou KI, Parisien M, Dai Q, Liu N, Diatchenko L, Sachleben JR, Pan T (2016) N(6)-Methyladenosine modification in a long noncoding RNA hairpin predisposes its conformation to protein binding. J Mol Biol 428:822–833. https://doi.org/10.1016/j.jmb.2015.08.021
Song H, Li H, Ding X, Li M, Shen H, Li Y, Zhang X, Xing L (2020) Long non-coding RNA FEZF1-AS1 facilitates non-small cell lung cancer progression via the ITGA11/miR-516b-5p axis. Int J Oncol 57:1333–1347. https://doi.org/10.3892/ijo.2020.5142
Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104. https://doi.org/10.1038/sj.cdd.4400476
Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619. https://doi.org/10.1016/0092-8674(93)90509-o
Qin Y, Li L, Luo E, Hou J, Yan G, Wang D, Qiao Y, Tang C (2020) Role of m6A RNA methylation in cardiovascular disease (review). Int J Mol Med 46:1958–1972. https://doi.org/10.3892/ijmm.2020.4746
Zhao K, Yang CX, Li P, Sun W, Kong XQ (2020) Epigenetic role of N6-methyladenosine (m6A) RNA methylation in the cardiovascular system. J Zhejiang Univ Sci B 21:509–523. https://doi.org/10.1631/jzus.B1900680
Zhang L, Wu YJ, Zhang SL (2019) Circulating lncRNA MHRT predicts survival of patients with chronic heart failure. J Geriatr Cardiol 16:818–821. https://doi.org/10.11909/j.issn.1671-5411.2019.11.006
This study was approved by The special projects of development in local science and technology guided by the central government (2016080802D113); Natural Science Foundation of Anhui Province (1808085MH281); and New Medicine of University of Science and Technology of China (WK9110000046).
Conflict of interest
The authors declare that they have no competing interests.
The study was approved by the Ethics Committee of The First Affiliated Hospital of USTC.
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Shen, W., Li, H., Su, H. et al. FTO overexpression inhibits apoptosis of hypoxia/reoxygenation-treated myocardial cells by regulating m6A modification of Mhrt. Mol Cell Biochem 476, 2171–2179 (2021). https://doi.org/10.1007/s11010-021-04069-6
- m6A modification
- Heart failure