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Editorial
. 2024 Jun 10;12(3):55.
doi: 10.21037/atm-24-54. Epub 2024 May 28.

A HIF-2α-dependent KMT2E-AS1/KMT2E axis orchestrates endothelial epigenetic and metabolic dysfunction in pulmonary hypertension

Sarah-Eve Lemay  1 , Steeve Provencher  1   2 , Sébastien Bonnet  1   2 , François Potus  1   2 , Olivier Boucherat  1   2
Affiliations
Editorial

A HIF-2α-dependent KMT2E-AS1/KMT2E axis orchestrates endothelial epigenetic and metabolic dysfunction in pulmonary hypertension

Sarah-Eve Lemay et al. Ann Transl Med. .
No abstract available

Keywords: Pulmonary arterial hypertension (PAH); hypoxia; long non-coding RNA (lncRNA); pulmonary artery endothelial cells (PAECs); vascular remodeling.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-24-54/coif). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Potential implications of the results presented in the study against background PAH therapy. (A) Graphic summary of results presented in the study. Under hypoxia or pseudohypoxia, HIF-2α activation in PAECs increases expression of the lncRNA KMT2E-AS1 and neighboring gene KMT2E. KMT2E-AS1 binds and stabilizes KMT2E leading to increase H3K4me3 deposition and transactivation of genes favoring metabolic adaptation and proliferation, including HIF-2α. This creates a feed-forward loop sustaining pathogenic endothelial activity and pulmonary vascular remodeling. A SNV (rs73184087) within a KMT2E intron was found to be associated with the risk of developing PH. SNV rs73184087 displays allele-specific binding to HIF-2α and long-range interaction with the shared lncRNA-KMT2E promoter. (B) Pathogenesis of PAH. PAH is characterized by vasoconstriction and vascular remodeling of small PAs leading to progressive increase in pulmonary vascular resistance, and consequently RV failure. Currently available treatments focus primarily on vasodilation rather than on vascular remodeling and offer only limited beneficial effects on survival. HIF-2α, hypoxia-inducible factor-2α; SNV, single nucleotide variant; PAEC, pulmonary artery endothelial cell; PASMC, pulmonary artery smooth muscle cell; PA, pulmonary artery; PAH, pulmonary arterial hypertension; RV, right ventricle; LV, left ventricle; PDE-5, phosphodiesterase-5; lncRNA, long non-coding RNA; PH, pulmonary hypertension.
See this image and copyright information in PMC

Comment on

  • Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.
    Tai YY, Yu Q, Tang Y, Sun W, Kelly NJ, Okawa S, Zhao J, Schwantes-An TH, Lacoux C, Torrino S, Al Aaraj Y, El Khoury W, Negi V, Liu M, Corey CG, Belmonte F, Vargas SO, Schwartz B, Bhat B, Chau BN, Karnes JH, Satoh T, Barndt RJ, Wu H, Parikh VN, Wang J, Zhang Y, McNamara D, Li G, Speyer G, Wang B, Shiva S, Kaufman B, Kim S, Gomez D, Mari B, Cho MH, Boueiz A, Pauciulo MW, Southgate L, Trembath RC, Sitbon O, Humbert M, Graf S, Morrell NW, Rhodes CJ, Wilkins MR, Nouraie M, Nichols WC, Desai AA, Bertero T, Chan SY. Tai YY, et al. Sci Transl Med. 2024 Jan 10;16(729):eadd2029. doi: 10.1126/scitranslmed.add2029. Epub 2024 Jan 10. Sci Transl Med. 2024. PMID: 38198571 Free PMC article.

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