Abstract
N6-methyladenosine (m6A) is emerging as an essential regulator in the progression of myocardial ischemia reperfusion (I/R) injury. However, the in-depth functions and mechanisms for m6A are still unclear. This work aimed to explore the potential functions and mechanisms for myocardial I/R injury. In this study, m6A methyltransferase WTAP and m6A modification level elevated in the hypoxia/reoxygenation (H/R) induced rat cardiomyocytes (H9C2) and I/R injury rat model. Bio-functional cellular experiments demonstrated that knockdown of WTAP remarkably released the proliferation and reduced the apoptosis and inflammatory cytokines induced by H/R. Moreover, exercise training alleviated WTAP level in exercise-trained rats. Mechanistically, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) revealed that a remarkable m6A modification site was found in the 3’-UTR of FOXO3a mRNA. Moreover, WTAP triggered the installation of m6A modification on FOXO3a mRNA through m6A reader YTHDF1, thereby enhancing the stability of FOXO3a mRNA. Collectively, WTAP/YTHDF1/m6A/FOXO3a axis regulates the myocardial I/R injury progression, which provides new insights for the treatment of myocardial injury.
Similar content being viewed by others
Data availability
No research data shared.
References
Regan B, O’Kennedy R, Collins D (2021) Advances in point-of-care testing for cardiovascular diseases. Adv Clin Chem 104:1–70
Krittanawong C, Narasimhan B, Wang Z, Hahn J, Virk HUH, Farrell AM et al (2021) Association between chocolate consumption and risk of coronary artery disease: a systematic review and meta-analysis. Eur J Prev Cardiol 28:e33–e5
Pan Q, Liu Y, Ma W, Kan R, Zhu H, Li D (2022) Cardioprotective Effects and possible mechanisms of Luteolin for Myocardial Ischemia-Reperfusion Injury: a systematic review and Meta-analysis of preclinical evidence. Front Cardiovasc Med 9:685998
He J, Liu D, Zhao L, Zhou D, Rong J, Zhang L et al (2022) Myocardial ischemia/reperfusion injury: mechanisms of injury and implications for management (review). Experimental and therapeutic medicine 23:430
Prem PN, Sivakumar B, Boovarahan SR, Kurian GA (2022) Recent advances in potential of Fisetin in the management of myocardial ischemia-reperfusion injury-A systematic review. Phytomedicine: Int J phytotherapy phytopharmacology 101:154123
Amani H, Habibey R, Hajmiresmail SJ, Latifi S, Pazoki-Toroudi H, Akhavan O (2017) Antioxidant nanomaterials in advanced diagnoses and treatments of ischemia reperfusion injuries. J Mater Chem B 5:9452–9476
Dai F, Wu Y, Lu Y, An C, Zheng X, Dai L et al (2020) Crosstalk between RNA m(6)a modification and non-coding RNA contributes to Cancer Growth and Progression. Mol therapy Nucleic acids 22:62–71
Liang Z, Kidwell RL, Deng H, Xie Q (2020) Epigenetic N6-methyladenosine modification of RNA and DNA regulates cancer. Cancer biology & medicine 17:9–19
Wang T, Kong S, Tao M, Ju S (2020) The potential role of RNA N6-methyladenosine in Cancer progression. Mol Cancer 19:88
Dai D, Wang H, Zhu L, Jin H, Wang X (2018) N6-methyladenosine links RNA metabolism to cancer progression. Cell Death Dis 9:124
Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z et al (2019) METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer 18:142
Song H, Feng X, Zhang H, Luo Y, Huang J, Lin M et al (2019) METTL3 and ALKBH5 oppositely regulate m(6)a modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes. Autophagy 15:1419–1437
Yang FY, Zhang L, Zheng Y, Dong H (2022) Dexmedetomidine attenuates ischemia and reperfusion-induced cardiomyocyte injury through p53 and forkhead box O3a (FOXO3a)/p53-upregulated modulator of apoptosis (PUMA) signaling signaling. Bioengineered 13:1377–1387
Zhang R, Li Y, Liu X, Qin S, Guo B, Chang L et al (2020) FOXO3a-mediated long non-coding RNA LINC00261 resists cardiomyocyte hypoxia/reoxygenation injury via targeting miR23b-3p/NRF2 axis. J Cell Mol Med 24:8368–8378
Zhao Y, Pei X, Liu Y, Xu Y, Peng M, Yang H (2021) [Down-regulation of miR-488 targeting to promote Jag1 expression inhibits hypoxia-reoxygenation myocardial H9c2 cell damage]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = chinese. J Med Genet 38:1199–1203
Xu H, Cheng J, Wang X, Liu H, Wang S, Wu J et al (2019) Resveratrol pretreatment alleviates myocardial ischemia/reperfusion injury by inhibiting STIM1-mediated intracellular calcium accumulation. J Physiol Biochem 75:607–618
Niu Y, Lin Z, Wan A, Chen H, Liang H, Sun L et al (2019) RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer 18:46
Yang F, Jin H, Que B, Chao Y, Zhang H, Ying X et al (2019) Dynamic m(6)a mRNA methylation reveals the role of METTL3-m(6)A-CDCP1 signaling axis in chemical carcinogenesis. Oncogene 38:4755–4772
Dong W, Bi J, Liu H, Yan D, He Q, Zhou Q et al (2019) Circular RNA ACVR2A suppresses bladder cancer cells proliferation and metastasis through miR-626/EYA4 axis. Mol Cancer 18:95
Parry TL, Starnes JW, O’Neal SK, Bain JR, Muehlbauer MJ, Honcoop A et al (2018) Untargeted metabolomics analysis of ischemia-reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats. Metabolomics: Official journal of the Metabolomic Society 14:8
Liu CY, Zhang YH, Li RB, Zhou LY, An T, Zhang RC et al (2018) LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription. Nat Commun 9:29
Deng X, Su R, Weng H, Huang H, Li Z, Chen J (2018) RNA N(6)-methyladenosine modification in cancers: current status and perspectives. Cell Res 28:507–517
Zeng C, Huang W, Li Y, Weng H (2020) Roles of METTL3 in cancer: mechanisms and therapeutic targeting. J Hematol Oncol 13:117
Li Y, Weng H, Frye M (2018) RNA modifications modulate gene expression during development, vol 361. Science, New York, NY, pp 1346–1349
Zheng W, Dong X, Zhao Y, Wang S, Jiang H, Zhang M et al (2019) Multiple functions and mechanisms underlying the role of METTL3 in human cancers. Front Oncol 9:1403
Li Y, Cao Y, Xiao J, Shang J, Tan Q, Ping F et al (2020) Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury. Cell Death Differ 27:2635–2650
Pefanis A, Ierino FL, Murphy JM, Cowan PJ (2019) Regulated necrosis in kidney ischemia-reperfusion injury. Kidney Int 96:291–301
Gui Y, Lu Q, Gu M, Wang M, Liang Y, Zhu X et al (2019) Fibroblast mTOR/PPARγ/HGF axis protects against tubular cell death and acute kidney injury. Cell Death Differ 26:2774–2789
Liu L, Wang Y, Wu J, Liu J, Qin Z, Fan H (2020) N(6)-Methyladenosine: a potential breakthrough for Human Cancer. Mol therapy Nucleic acids 19:804–813
Wang J, Zhang J, Ma Y, Zeng Y, Lu C, Yang F et al (2021) WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m(6)a modification of ATF4 mRNA. Aging 13:11135–11149
Zhao X, Yang L, Qin L Methyltransferase-like 3 (METTL3) attenuates cardiomyocyte apoptosis with myocardial ischemia-reperfusion (I/R) injury through mir-25-3p and miR-873-5p. Cell biology international 2021.
Feehan RP, Shantz LM (2016) Negative regulation of the FOXO3a transcription factor by mTORC2 induces a pro-survival response following exposure to ultraviolet-B irradiation. Cell Signal 28:798–809
Lavie CJ, Ozemek C, Carbone S, Katzmarzyk PT, Blair SN (2019) Sedentary behavior, Exercise, and Cardiovascular Health. Circul Res 124:799–815
Adams V, Linke A (2019) Impact of exercise training on cardiovascular disease and risk. Biochim et Biophys acta Mol basis disease 1865:728–734
Adams V, Reich B, Uhlemann M, Niebauer J (2017) Molecular effects of exercise training in patients with cardiovascular disease: focus on skeletal muscle, endothelium, and myocardium. Am J Physiol Heart Circ Physiol 313:H72–h88
Acknowledgements
No.
Funding
No funding was received.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors declare no conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
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
Wang, H., Fu, L., Li, Y. et al. m6A methyltransferase WTAP regulates myocardial ischemia reperfusion injury through YTHDF1/FOXO3a signaling. Apoptosis 28, 830–839 (2023). https://doi.org/10.1007/s10495-023-01818-4
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-023-01818-4