Science and Research

Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure. Homoeostatic effects of flow-activated transcription factor Kruppel-like factor 2 (KLF2) are compromised in PAH. Here, we show that KLF2-induced exosomal microRNAs, miR-181a-5p and miR-324-5p act together to attenuate pulmonary vascular remodelling and that their actions are mediated by Notch4 and ETS1 and other key regulators of vascular homoeostasis. Expressions of KLF2, miR-181a-5p and miR-324-5p are reduced, while levels of their target genes are elevated in pre-clinical PAH, idiopathic PAH and heritable PAH with missense p.H288Y KLF2 mutation. Therapeutic supplementation of miR-181a-5p and miR-324-5p reduces proliferative and angiogenic responses in patient-derived cells and attenuates disease progression in PAH mice. This study shows that reduced KLF2 signalling is a common feature of human PAH and highlights the potential therapeutic role of KLF2-regulated exosomal miRNAs in PAH and other diseases associated with vascular remodelling.

  • Sindi, H. A.
  • Russomanno, G.
  • Satta, S.
  • Abdul-Salam, V. B.
  • Jo, K. B.
  • Qazi-Chaudhry, B.
  • Ainscough, A. J.
  • Szulcek, R.
  • Jan Bogaard, H.
  • Morgan, C. C.
  • Pullamsetti, S. S.
  • Alzaydi, M. M.
  • Rhodes, C. J.
  • Piva, R.
  • Eichstaedt, C. A.
  • Grunig, E.
  • Wilkins, M. R.
  • Wojciak-Stothard, B.

Keywords

  • Adult
  • Aged
  • Animals
  • Cell Proliferation/genetics
  • Disease Models, Animal
  • Disease Progression
  • Endothelial Cells
  • Exosomes/genetics/metabolism
  • Female
  • Gene Expression Regulation
  • Genetic Therapy/*methods
  • Humans
  • Kruppel-Like Transcription Factors/genetics/*metabolism
  • Lung/blood supply/cytology/pathology
  • Male
  • Mice
  • MicroRNAs/metabolism/*therapeutic use
  • Middle Aged
  • Mutation, Missense
  • Primary Cell Culture
  • Pulmonary Arterial Hypertension/genetics/pathology/*therapy
  • Pulmonary Artery/cytology/pathology
  • Signal Transduction/genetics
  • Vascular Remodeling/genetics
  • Young Adult
Publication details
DOI: 10.1038/s41467-020-14966-x
Journal: Nat Commun
Pages: 1185 
Number: 1
Work Type: Original
Location: UGMLC
Disease Area: PH
Partner / Member: JLU, MPI-BN
Access-Number: 32132543
See publication on PubMed

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