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S84 Identification of MIR-124a as a major regulator of enhanced endothelial cell glycolysis in pulmonary arterial hypertension
  1. P Caruso1,
  2. BJ Dunmore1,
  3. K Schlosser2,
  4. S Schoors3,
  5. C Dos Santos2,
  6. C Perez-Iratxeta2,
  7. JR Lavoie2,
  8. L Long1,
  9. L Hurst1,
  10. ML Ormiston4,
  11. A Hata5,
  12. P Carmeliet3,
  13. DJ Stewart2,
  14. NW Morrell1
  1. 1University of Cambridge, Cambridge, UK
  2. 2Ottawa Hospital Research Institute and the University of Ottawa, Ottawa, Canada
  3. 3Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Centre, Leuven, Belgium
  4. 4Queen’s University, Kingston, Canada
  5. 5Cardiovascular Research Institute, University of California, San Francisco, USA


Introduction Pulmonary arterial hypertension (PAH) is a rare desease characterised by profound vascular abnormalities in the peripheral arteries of the lung, leading to a progressive increase in pulmonary vascular resistance, right heart failure and death. The disease exists in several forms including a heritable form (HPAH) caused primarily by mutations in bone morphogenetic protein receptor type 2 (BMPR2) and an idiopathic form (IPAH). Endothelial cell (EC) dysfunction is considered a critical initiating factor in the pathobiology of PAH, manifested by increased susceptibility to apoptosis, heightened permeability and enhanced endothelial proliferation. Substantial changes in bioenergetics of ECs, including higher rates of glycolysis, have been reported in PAH patients. However, the mechanisms underlying alterations in energy production have not been identified.

Methods We measured glycolysis in blood outgrowth endothelial cells (BOECs) from HPAH patients carrying mutations in BMPR2 and IPAH patients to confirm the metabolic abnormalities previously. We also employed an unbiased genome-wide microarray and proteomic screening approach to detect miRNAs and proteins dysregulated in the same groups to determine the mechanisms underlying abnormal endothelial glycolysis.

Results HPAH and IPAH BOECs recapitulated the metabolic phenotype previously observed in PAECs. These alterations were found to be associated with the downregulation of miR-124 and the upregulation of its known target, splicing factor polypyrimidine-tract-binding protein (PTBP1). We also demonstrated that increased PTBP1 promotes the switching in expression of two forms of pyruvate kinase, PKM1 and PKM2, resulting in an increase of aerobic glycolysis, consequently increasing cell proliferation (mechanism schematized in Figure 1). Overexpression of miR-124, or siRNA silencing of PTPB1, restoring normal expression levels of PKM2, also restored normal proliferation and glycolysis in HPAH BOECs. Finally, we observed reduced miR-124 and increased PTPB1 and PKM2 expression in a well-established rat model of PAH, characterised by endothelial proliferation, supporting the presence of this mechanism in vivo.

Conclusions Loss of function of BMPR2 results in the downregulation of miR-124 and consequently in the glycolytic abnormalities reported in PAH ECs. Therefore, the manipulation of this miRNA, or its targets, could represent a novel and effective strategy to achieve clinical benefits in the treatment of PAH.

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