Abstract
Myocardial infarction (MI) is the main cause of heart failure (HF). N6-methyladenosine (m6A) methylation is associated with the progression of HF. The study aimed to explore whether METTL3 regulates ferroptosis of cardiomyocytes in HF. We evaluated ferroptosis by detecting lactic dehydrogenase (LDH) release, lipid reactive oxygen species (ROS), Fe2+, glutathione (GSH), and malonaldehyde (MDA) levels. M6A methylation was assessed using methylated RNA immunoprecipitation assay. The binding relationship was assessed using RNA immunoprecipitation assays. The mRNA stability was assessed using actinomycin D treatment. The results showed that METTL3 was upregulated in oxygen glucose deprivation/recovery (OGD/R) cells, which knockdown suppressed OGD/R-induced ferroptosis. Moreover, METTL3 could bind to SLC7A11, promoting m6A methylation of SLC7A11. Silencing of SLC7A11 abrogated the suppression of ferroptosis induced by METTL3 knockdown. Additionally, YTHDF2 was the reader that recognized the methylation of SLC7A11, reducing the stability of SLC7A11. The silencing of METTL3 inhibited OGD/R-induced ferroptosis by suppressing the m6A methylation of SLC7A11, which is recognized by YTHDF2. The findings suggested that METTL3-mediated ferroptosis might be a new strategy for MI-induced HF therapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
References
Bahit MC, Kochar A, Granger CB (2018) Post-myocardial infarction heart failure. JACC Heart Fail 6(3):179–186. https://doi.org/10.1016/j.jchf.2017.09.015
Berulava T, Buchholz E, Elerdashvili V, Pena T, Islam MR, Lbik D et al (2020) Changes in m6A RNA methylation contribute to heart failure progression by modulating translation. Eur J Heart Fail 22(1):54–66. https://doi.org/10.1002/ejhf.1672
Borlaug BA (2020) Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol 17(9):559–573. https://doi.org/10.1038/s41569-020-0363-2
Chen X, Xu S, Zhao C, Liu B (2019) Role of TLR4/NADPH oxidase 4 pathway in promoting cell death through autophagy and ferroptosis during heart failure. Biochem Biophys Res Commun 516(1):37–43. https://doi.org/10.1016/j.bbrc.2019.06.015
Chien CS, Li JY, Chien Y, Wang ML, Yarmishyn AA, Tsai PH et al (2021) METTL3-dependent N6-methyladenosine RNA modification mediates the atherogenic inflammatory cascades in vascular endothelium. Proc Natl Acad Sci U S A 118(7):e2025070118. https://doi.org/10.1073/pnas.2025070118
Cruz MS, da Silva AMG, de Souza KSC, Luchessi AD, Silbiger VN (2020) miRNAs emerge as circulating biomarkers of post-myocardial infarction heart failure. Heart Fail Rev 25(2):321–329. https://doi.org/10.1007/s10741-019-09821-1
Del Re DP, Amgalan D, Linkermann A, Liu Q, Kitsis RN (2019) Fundamental mechanisms of regulated cell death and implications for Heart Disease. Physiol Rev 99(4):1765–1817. https://doi.org/10.1152/physrev.00022.2018
Dixit D, Prager BC, Gimple RC, Poh HX, Wang Y, Wu Q et al (2021) The RNA m6A reader YTHDF2 maintains Oncogene expression and is a targetable dependency in Glioblastoma Stem cells. Cancer Discov 11(2):480–499. https://doi.org/10.1158/2159-8290.CD-20-0331
Dorn LE, Lasman L, Chen J, Xu X, Hund TJ, Medvedovic M et al (2019) The N6-Methyladenosine mRNA methylase METTL3 controls Cardiac Homeostasis and Hypertrophy. Circulation 139(4):533–545. https://doi.org/10.1161/CIRCULATIONAHA.118.036146
Fan Z, Yang G, Zhang W, Liu Q, Liu G, Liu P et al (2021) Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2-dependent silencing of SLC7A11. J Cell Mol Med 25(21):10197–10212. https://doi.org/10.1111/jcmm.16957
Fang X, Wang H, Han D, Xie E, Yang X, Wei J et al (2019) Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A 116(7):2672–2680. https://doi.org/10.1073/pnas.1821022116
Fang X, Cai Z, Wang H, Han D, Cheng Q, Zhang P et al (2020) Loss of Cardiac Ferritin H facilitates Cardiomyopathy via Slc7a11-Mediated ferroptosis. Circ Res 127(4):486–501. https://doi.org/10.1161/CIRCRESAHA.120.316509
Guan X, Li Z, Zhu S, Cheng M, Ju Y, Ren L et al (2021) Galangin attenuated cerebral ischemia-reperfusion injury by inhibition of ferroptosis through activating the SLC7A11/GPX4 axis in gerbils. Life Sci 264:118660. https://doi.org/10.1016/j.lfs.2020.118660
Hu H, Chen Y, Jing L, Zhai C, Shen L (2021) The Link between Ferroptosis and Cardiovascular diseases: a novel target for treatment. Front Cardiovasc Med 8:710963. https://doi.org/10.3389/fcvm.2021.710963
Ilieșiu AM, Hodorogea AS (2018) Treatment of Heart failure with preserved ejection fraction. Adv Exp Med Biol 1067:67–87. https://doi.org/10.1007/5584_2018_149
Jenča D, Melenovský V, Stehlik J, Staněk V, Kettner J, Kautzner J et al (2021) Heart failure after myocardial infarction: incidence and predictors. ESC Heart Fail 8(1):222–237. https://doi.org/10.1002/ehf2.13144
Koppula P, Zhuang L, Gan B (2021) Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell 12(8):599–620. https://doi.org/10.1007/s13238-020-00789-5
Li N, Jiang W, Wang W, Xiong R, Wu X, Geng Q (2021) Ferroptosis and its emerging roles in cardiovascular diseases. Pharmacol Res 166:105466. https://doi.org/10.1016/j.phrs.2021.105466
Li N, Yi X, He Y, Huo B, Chen Y, Zhang Z et al (2022) Targeting Ferroptosis as a Novel Approach to alleviate aortic dissection. Int J Biol Sci 18(10):4118–4134. https://doi.org/10.7150/ijbs.72528
Lin Y, Shen X, Ke Y, Lan C, Chen X, Liang B et al (2022) Activation of osteoblast ferroptosis via the METTL3/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss. FASEB J 36(3):e22147. https://doi.org/10.1096/fj.202101610R
Ma WQ, Sun XJ, Zhu Y, Liu NF (2021) Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects. Free Radic Biol Med 165:229–242. https://doi.org/10.1016/j.freeradbiomed.2021.01.033
Melenovsky V, Petrak J, Mracek T, Benes J, Borlaug BA, Nuskova H et al (2017) Myocardial iron content and mitochondrial function in human heart failure: a direct tissue analysis. Eur J Heart Fail 19(4):522–530. https://doi.org/10.1002/ejhf.640
Pietrangelo A (2010) Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 139(2):393–408. 408.e1-2
Qin Y, Li L, Luo E, Hou J, Yan G, Wang D et al (2020) Role of m6A RNA methylation in cardiovascular disease (review). Int J Mol Med 46(6):1958–1972. https://doi.org/10.3892/ijmm.2020.4746
Qin Y, Qiao Y, Li L, Luo E, Wang D, Yao Y et al (2021) The m6A methyltransferase METTL3 promotes hypoxic pulmonary arterial hypertension. Life Sci 274:119366. https://doi.org/10.1016/j.lfs.2021.119366
Qiu Y, Cao Y, Cao W, Jia Y, Lu N (2020) The application of ferroptosis in diseases. Pharmacol Res 159:104919. https://doi.org/10.1016/j.phrs.2020.104919
Tomasoni D, Adamo M, Lombardi CM, Metra M (2019) Highlights in heart failure. ESC Heart Fail 6(6):1105–1127. https://doi.org/10.1002/ehf2.12555
Vausort M, Niedolistek M, Lumley AI, Oknińska M, Paterek A, Mączewski M et al (2022) Regulation of N6-Methyladenosine after myocardial infarction. Cells 11(15):2271. https://doi.org/10.3390/cells11152271
Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X et al (2016) Ferroptosis: process and function. Cell Death Differ 23(3):369–379. https://doi.org/10.1038/cdd.2015.158
Xu Y, Lv D, Yan C, Su H, Zhang X, Shi Y et al (2022) METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification. Cancer Cell Int 22(1):11. https://doi.org/10.1186/s12935-021-02433-6
Yu Y, Yan Y, Niu F, Wang Y, Chen X, Su G et al (2021) Ferroptosis: a cell death connecting oxidative stress, inflammation and cardiovascular diseases. Cell Death Discov 7(1):193. https://doi.org/10.1038/s41420-021-00579-w
Zhang B, Xu Y, Cui X, Jiang H, Luo W, Weng X et al (2021) Alteration of m6A RNA methylation in heart failure with preserved ejection fraction. Front Cardiovasc Med 8:647806. https://doi.org/10.3389/fcvm.2021.647806
Zhang X, Zheng C, Gao Z, Chen H, Li K, Wang L et al (2022) SLC7A11/xCT prevents Cardiac Hypertrophy by inhibiting ferroptosis. Cardiovasc Drugs Ther 36(3):437–447. https://doi.org/10.1007/s10557-021-07220-z
Zhao Y, Shi Y, Shen H, Xie W (2020) m6A-binding proteins: the emerging crucial performers in epigenetics. J Hematol Oncol 13(1):35. https://doi.org/10.1186/s13045-020-00872-8
Acknowledgements
Not applicable.
Funding
Not applicable.
Author information
Authors and Affiliations
Contributions
All authors participated in the design, interpretation of the studies and analysis of the data and review of the manuscript. ZT drafted the work and revised it critically for important intellectual content; XH and HM were responsible for the acquisition, analysis, or interpretation of data for the work; ZZ made substantial contributions to the conception or design of the work.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Tang, Z., Huang, X., Mei, H. et al. Silencing of METTL3 suppressed ferroptosis of myocardial cells by m6A modification of SLC7A11 in a YTHDF2 manner. J Bioenerg Biomembr 56, 149–157 (2024). https://doi.org/10.1007/s10863-024-10006-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10863-024-10006-1