Article Text

PDF

E microRNA-140-5p and SMURF1 Regulate Pulmonary Arterial Hypertension
  1. Alexander MK Rothman1,2,
  2. Nadine D Arnold1,
  3. Josephine A Pickworth1,
  4. James Iremonger1,
  5. Loredana Ciuclan3,
  6. Robert Allen3,
  7. Sabine Guth-Gundel4,
  8. Mark Southwood5,
  9. Nicholas W Morrell5,
  10. Matthew Thomas6,
  11. Sheila E Francis1,
  12. David J Rowlands3,
  13. Allan Lawrie1
  1. 1Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
  2. 2Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
  3. 3Novartis Institutes for Biomedical Research, Cambridge, MA, USA
  4. 4Novartis Institutes for Biomedical Research, Basel, Switzerland
  5. 5Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge, UK
  6. 6AstraZeneca R&D, Respiratory, Inflammation and Autoimmunity (RIA) Innovative Medicines, Building AC461, SE-431 83 Mölndal, Sweden

Abstract

Background Clinical therapies for the treatment of pulmonary arterial hypertension (PAH) target vasoconstriction. However, the proliferative pulmonary vascular remodelling that drives disease persists contributing to significant patient morbidity and mortality. MicroRNA (miR) are short non-coding RNA that mediate post-transcriptional regulation of mRNA targets. We hypothesise that dysregulation of miR leads to de-repression of cellular targets central to disease pathogenesis.

Objective To identify dysregulated circulating miR in patients with PAH, determine their phenotypic effect using in vitro and in vivo models and identify key mechanistic regulators that may represent novel therapeutic targets.

Methods and results Expression of miR-140-5p was reduced in whole blood samples from patients with PAH. Reduced expression of miR-140-5p at the time of diagnosis identified patients with adverse clinical characteristics. Transfection with miR-140-5p inhibitor resulted in increased proliferation PASMC and de-repression of key targets. Nebulised delivery of miR-140-5p mimic attenuated progression of established PAH in the SuHx rat model. Network and pathway analysis identified SMAD Specific E3 Ubiquitin Protein Ligase 1 (SMURF1) as a key miR-140-5p target. Whole blood mRNA and pulmonary vascular immunoreactivity of SMURF1 was increased in patients with PAH implicating SMURF1 in the pathology of human disease. Direct regulation of SMURF1 by miR-140-5p was demonstrated in-vitro by 3’UTR luciferase activity. Both miR-140-5p mimic and SMURF1 siRNA increased BMP response element activity identifying SMURF1 as a key negative regulator of BMP signalling in PASMC. Genetic ablation of SMURF1 in C57BL6 mice conferred allele dependent protection from SuHx induced PAH.

Conclusions These studies suggest that miR-140 and SMURF1 are key regulators of BMP signalling and disease pathology in PAH and highlight SMURF1 as a potential novel therapeutic target.

  • Pulmonary hypertension
  • microRNA
  • SMURF1

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.