MicroRNA-374b induces endothelial-to-mesenchymal transition and early lesion formation through the inhibition of MAPK7 signaling

Byambasuren Vanchin, Emma Offringa, Julian Friedrich, Marja G. L. Brinker, Bianca Kiers, Alexandre C. Pereira, Martin C. Harmsen, Jan-Renier A. J. Moonen, Guido Krenning*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Endothelial-mesenchymal transition occurs during intimal hyperplasia and neointima formation via mechanisms that are incompletely understood. Endothelial MAPK7 signaling is a key mechanosensitive factor that protects against endothelial-mesenchymal transition, but its signaling activity is lost in vessel areas that are undergoing pathological remodeling. At sites of vascular remodeling in mice and pigs, endothelial MAPK7 signaling was lost. The TGF beta-induced microRNA-374b targets MAPK7 and its downstream effectors in endothelial cells, and its expression induces endothelial-mesenchymal transition. Gain-of-function experiments, where endothelial MAPK7 signaling was restored, precluded endothelial-mesenchymal transition. In human coronary artery disease, disease severity is associated with decreased MAPK7 expression levels and increased miR-374b expression levels. Endothelial-mesenchymal transition occurs in intimal hyperplasia and early lesion formation and is governed in part by microRNA-374b-induced silencing of MAPK7 signaling. Restoration of MAPK7 signaling abrogated these pathological effects in endothelial cells expressing miR-374b. Thus, our data suggest that the TGF beta-miR-374b-MAPK7 axis plays a key role in the induction of endothelial-mesenchymal transition during intimal hyperplasia and early lesion formation and might pose an interesting target for antiatherosclerosis therapy. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Original languageEnglish
Pages (from-to)456-470
Number of pages15
JournalJOURNAL OF PATHOLOGY
Volume247
Issue number4
Early online date22-Nov-2018
DOIs
Publication statusPublished - Apr-2019

Keywords

  • microRNA
  • MAPK7
  • shear stress
  • endothelial-mesenchymal transition (EndMT)
  • atherosclerosis
  • LAMINAR SHEAR-STRESS
  • HEART-ASSOCIATION
  • AMERICAN-COLLEGE
  • GROWTH-FACTOR
  • ATHEROSCLEROSIS
  • ERK5
  • EXPRESSION
  • DISEASE
  • DYSFUNCTION
  • ACTIVATION

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