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Upregulation of eIF2α by m6A modification accelerates the proliferation of pulmonary artery smooth muscle cells in MCT-induced pulmonary arterial hypertension rats

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Abstract

Pulmonary arterial hypertension (PAH) is a malignant cardiovascular disease. Eukaryotic initiation factor 2α (eIF2α) plays an important role in the proliferation of pulmonary artery smooth muscle cells (PASMCs) in hypoxia-induced pulmonary hypertension (HPH) rats. However, the regulatory mechanism of eIF2α remains poorly understood in PAH rats. Here, we discover eIF2α is markedly upregulated in monocrotaline (MCT)-induced PAH rats, eIF2α can be upregulated by mRNA methylation, and upregulated eIF2α can promote PASMC proliferation in MCT-PAH rats. GSK2606414, eIF2α inhibitor, can downregulate the expression of eIF2α and alleviate PASMC proliferation in MCT-PAH rats. And we further discover the mRNA of eIF2α has a common sequence with N 6-methyladenosine (m6A) modification by bioinformatics analysis, and the expression of METTL3, WTAP, and YTHDF1 is upregulated in MCT-PAH rats. These findings suggest a potentially novel mechanism by which eIF2α is upregulated by m6A modification in MCT-PAH rats, which is involved in the pathogenesis of PAH.

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References

  1. Poch D, Mandel J. Pulmonary hypertension. Ann Intern Med. 2021;174(4):ITC49–64.

    Article  PubMed  Google Scholar 

  2. Burki TK. Pharmacotherapy for pulmonary arterial hypertension. Lancet Respir Med. 2020;8(11): e81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Parikh V, Bhardwaj A, Nair A. Pharmacotherapy for pulmonary arterial hypertension. J Thorac Dis. 2019;11(Suppl 14):S1767–81.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hassoun PM. Pulmonary arterial hypertension. N Engl J Med. 2021;385(25):2361–76.

    Article  CAS  PubMed  Google Scholar 

  5. Baird TD, Wek RC. Eukaryotic initiation factor 2 phosphorylation and translational control in metabolism. Adv Nutr. 2012;3(3):307–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Donnelly N, Gorman AM, Gupta S, et al. The eIF2alpha kinases: their structures and functions. Cell Mol Life Sci. 2013;70(19):3493–511.

    Article  CAS  PubMed  Google Scholar 

  7. Zheng Q, Ye J, Cao J. Translational regulator eIF2alpha in tumor. Tumour Biol. 2014;35(7):6255–64.

    Article  CAS  PubMed  Google Scholar 

  8. Guo L, Li Y, Tian Y, et al. eIF2alpha promotes vascular remodeling via autophagy in monocrotaline-induced pulmonary arterial hypertension rats. Drug Des Devel Ther. 2019;13:2799–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang AP, Li XH, Yang YM, et al. A critical role of the mTOR/eIF2alpha pathway in hypoxia-induced pulmonary hypertension. PLoS One. 2015;10(6): e0130806.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Machnicka MA, Milanowska K, Osman Oglou O, et al. MODOMICS: a database of RNA modification pathways–2013 update. Nucleic Acids Res. 2013;41(Database issue):262–7.

    Google Scholar 

  11. Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci U S A. 1974;71(10):3971–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Furuichi Y, Morgan M, Shatkin AJ, et al. Methylated, blocked 5 termini in HeLa cell mRNA. Proc Natl Acad Sci U S A. 1975;72(5):1904–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lavi S, Shatkin AJ. Methylated simian virus 40-specific RNA from nuclei and cytoplasm of infected BSC-1 cells. Proc Natl Acad Sci U S A. 1975;72(6):2012–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Adams JM, Cory S. Modified nucleosides and bizarre 5′-termini in mouse myeloma mRNA. Nature. 1975;255(5503):28–33.

    Article  CAS  PubMed  Google Scholar 

  15. Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18(1):31–42.

    Article  CAS  PubMed  Google Scholar 

  16. Fu Y, Dominissini D, Rechavi G, et al. Gene expression regulation mediated through reversible m(6)A RNA methylation. Nat Rev Genet. 2014;15(5):293–306.

    Article  CAS  PubMed  Google Scholar 

  17. Huang J, Sun W, Wang Z, et al. FTO suppresses glycolysis and growth of papillary thyroid cancer via decreasing stability of APOE mRNA in an N6-methyladenosine-dependent manner. J Exp Clin Cancer Res. 2022;41(1):42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Raudvere U, Kolberg L, Kuzmin I, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47(W1):W191–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang X, Zhao BS, Roundtree IA, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161(6):1388–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yu G, Wang LG, Han Y, et al. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Du A, Li S, Zhou Y, et al. M6A-mediated upregulation of circMDK promotes tumorigenesis and acts as a nanotherapeutic target in hepatocellular carcinoma. Mol Cancer. 2022;21(1):109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang Z, Wang T, Wu D, et al. RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer. J Exp Clin Cancer Res. 2020;39(1):203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yin H, Zhang X, Yang P, et al. RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming. Nat Commun. 2021;12(1):1394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zeng Y, Huang T, Zuo W, et al. Integrated analysis of m(6)A mRNA methylation in rats with monocrotaline-induced pulmonary arterial hypertension. Aging (Albany NY). 2021;13(14):18238–56.

    Article  CAS  PubMed  Google Scholar 

  25. Liu P, Zhang A, Ding Z, et al. m(6)A Modification-mediated GRAP regulates vascular remodeling in hypoxic pulmonary hypertension. Am J Respir Cell Mol Biol. 2022;67(5):574–88.

    Article  CAS  PubMed  Google Scholar 

  26. Zhou XL, Huang FJ, Li Y, et al. SEDT2/METTL14-mediated m6A methylation awakening contributes to hypoxia-induced pulmonary arterial hypertension in mice. Aging (Albany NY). 2021;13(5):7538–48.

    Article  CAS  PubMed  Google Scholar 

  27. Shihan MH, Novo SG, Le Marchand SJ, et al. A simple method for quantitating confocal fluorescent images. Biochem Biophys Rep. 2021;25(2405-5808 (Electronic)):100916.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou W, Liu K, Zeng L, et al. Targeting VEGF-A/VEGFR2 Y949 signaling-mediated vascular permeability alleviates hypoxic pulmonary hypertension. Circulation. 2022;146(24):1855–81.

    Article  CAS  PubMed  Google Scholar 

  29. Shivaraju M, Chitta UK, Grange RMH, et al. Airway stem cells sense hypoxia and differentiate into protective solitary neuroendocrine cells. Science. 2021;371(6524):52–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu S, Zhang S, Wu X, et al. m(6)A RNA methylation in cardiovascular diseases. Mol Ther. 2020;28(10):2111–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ping XL, Sun BF, Wang L, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24(2):177–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yang X, Zhang S, He C, et al. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol Cancer. 2020;19(1):46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hu L, Wang J, Huang H, et al. YTHDF1 regulates pulmonary hypertension through translational control of MAGED1. Am J Respir Crit Care Med. 2021;203(9):1158–72.

    Article  CAS  PubMed  Google Scholar 

  34. Han Z, Wang X, Xu Z, et al. ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1. Theranostics. 2021;11(6):3000–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dorn LE, Lasman L, Chen J, et al. The N(6)-Methyladenosine mRNA methylase METTL3 controls cardiac homeostasis and hypertrophy. Circulation. 2019;139(4):533–45.

    Article  CAS  PubMed  Google Scholar 

  36. Zhou Y, Song K, Tu B, et al. METTL3 boosts glycolysis and cardiac fibroblast proliferation by increasing AR methylation. Int J Biol Macromol. 2022;223(Pt A):899–915.

    Article  CAS  PubMed  Google Scholar 

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Funding

This project was supported by the National Natural Science Foundation of China (grant number 81600040 to Wang AP), and the Natural Science Foundation of the Province of Hunan (grant number 2021JJ30601 to Wang AP), Key Program of Education Department of Hunan Province (grant number 21A0274 to Wang AP), Research project of Health Commission of Hunan Province (grant number 202204114218 to Liang N).

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Author notes

  1. Jing Zhang and Wen-Qian Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Institute of Neuroscience Research, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Jing Zhang, Wen-Qian Huang, Yu-Rong Zhang, Nan-Ping Li, Gang-Kai Tan & Ai-Ping Wang

  2. Institute of Clinical Research, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, People’s Republic of China

    Wen-Qian Huang & Ai-Ping Wang

  3. Department of Blood Transfusion, the First Affiliated of Hainan Medical University, Haikou, 570102, Hainan, People’s Republic of China

    Wen-Qian Huang

  4. Department of Anesthesiology, Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, People’s Republic of China

    Na Liang, Nan-Ping Li & Gang-Kai Tan

  5. Department of Pathology, First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Shao-Xin Gong

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  1. Jing Zhang
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Correspondence to Shao-Xin Gong or Ai-Ping Wang.

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Zhang, J., Huang, WQ., Zhang, YR. et al. Upregulation of eIF2α by m6A modification accelerates the proliferation of pulmonary artery smooth muscle cells in MCT-induced pulmonary arterial hypertension rats. J. of Cardiovasc. Trans. Res. (2023). https://doi.org/10.1007/s12265-023-10458-7

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