Science and Research

Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation. DNA was extracted from cultured PEC from idiopathic PAH (n = 11), heritable PAH (n = 10) and controls (n = 18). DNA methylation was assessed using the Illumina HumanMethylation450 Assay. After normalization, samples and probes were clustered according to their methylation profile. Differential clusters were functionally analyzed using bioinformatics tools. Unsupervised hierarchical clustering allowed the identification of two clusters of probes that discriminates controls and PAH patients. Among 147 differential methylated promoters, 46 promoters coding for proteins or miRNAs were related to lipid metabolism. Top 10 up and down-regulated genes were involved in lipid transport including ABCA1, ABCB4, ADIPOQ, miR-26A, BCL2L11. NextBio meta-analysis suggested a contribution of ABCA1 in PAH. We confirmed ABCA1 mRNA and protein downregulation specifically in PAH PEC by qPCR and immunohistochemistry and made the proof-of-concept in an experimental model of the disease that its targeting may offer novel therapeutic options. In conclusion, DNA methylation analysis identifies a set of genes mainly involved in lipid transport pathway which could be relevant to PAH pathophysiology.

  • Hautefort, A.
  • Chesne, J.
  • Preussner, J.
  • Pullamsetti, S. S.
  • Tost, J.
  • Looso, M.
  • Antigny, F.
  • Girerd, B.
  • Riou, M.
  • Eddahibi, S.
  • Deleuze, J. F.
  • Seeger, W.
  • Fadel, E.
  • Simonneau, G.
  • Montani, D.
  • Humbert, M.
  • Perros, F.

Keywords

  • ABC transporters
  • DNA methylation
  • endothelial cells
  • epigenetic
  • pulmonary arterial hypertension
  • grants and personal fees from Bayer, grants and personal fees from GSK, personal
  • fees from Novartis, personal fees from Pfizer, outside the submitted work
  • Pr.
  • Simonneau reports grants and personal fees from Actelion, grants and personal
  • fees from Bayer, grants and personal fees from GSK, personal fees from Pfizer,
  • outside the submitted work
  • Pr. Seeger has received honoraria for consultant
  • activities from Bayer and Novartis, and lecture fees from Actelion, Bayer,
  • Pfizer
  • Dr. Girerd reports personal fees from Actelion, personal fees from Bayer,
  • personal fees from GSK, personal fees from Pfizer, outside the submitted work
  • Dr. MONTANI reports grants and personal fees from Actelion, grants and personal
  • fees from Bayer, personal fees from BMS, personal fees from GSK, personal fees
  • from Novartis, personal fees from Pfizer, outside the submitted work
  • Other
  • authors have nothing to disclose.
Publication details
DOI: 10.18632/oncotarget.18031
Journal: Oncotarget
Pages: 52995-53016 
Number: 32
Work Type: Original
Location: UGMLC
Disease Area: PH
Partner / Member: JLU, MPI-BN
Access-Number: 28881789
See publication on PubMed

DZL Engagements

chevron-down