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MicroRNA-155 controls pulmonary artery fibroblast cell signalling and proliferation in a knockout mouse model: A role in pulmonary arterial hypertension

Neil McGlinchey, Connor Bradley, Charles McSharry, Andrew Peacock, David Welsh
European Respiratory Journal 2014 44: P2359; DOI:
Neil McGlinchey
1Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, United Kingdom
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Connor Bradley
1Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, United Kingdom
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Charles McSharry
2Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
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Andrew Peacock
1Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, United Kingdom
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David Welsh
1Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, United Kingdom
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Abstract

Background

Fibroblast proliferation mediated by p38 mitogen-activated protein kinase (p38MAPK) signalling contributes to adventitial thickening in experimental models of pulmonary arterial hypertension (PAH). MicroRNA-155 (miR-155) over expression can down regulate Smad5, a key signalling molecule in the Bone Morphogenetic Protein type-2 receptor (BMPR2) pathway, thereby potentially mimicking the loss-of-function BMPR2 mutations that can cause PAH.

Aims

We hypothesised that miR-155 down regulation would protect against enhanced hypoxic fibroblast proliferation by altering Smad5 and p38MAPK pathway activity.

Methods

Pulmonary adventitial fibroblasts (PAFs) isolated from miR-155 knockout (miR-155-/-) and wild-type (WT) mice were cultured in normoxia and hypoxia at various serum concentrations. Smad5 and p38MAPK expression was detected by Western blotting. Proliferation was assessed by [3H] Thymidine incorporation.

Results

miR-/- fibroblasts showed less p38 MAPK activity (phosphorylation) in hypoxia (see Fig. 1) and increased Smad5 signalling compared with WT cells.

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WT fibroblasts proliferated to a higher degree in hypoxic conditions compared to normoxic controls. This effect was abrogated in the miR-155-/- cells.

Conclusion

miR-155 may play a role in the pathogenesis of PAH via its control of key signalling pathways linked to pulmonary vascular remodelling.

  • Pulmonary hypertension
  • Cell biology
  • Epigenetics
  • © 2014 ERS
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MicroRNA-155 controls pulmonary artery fibroblast cell signalling and proliferation in a knockout mouse model: A role in pulmonary arterial hypertension
Neil McGlinchey, Connor Bradley, Charles McSharry, Andrew Peacock, David Welsh
European Respiratory Journal Sep 2014, 44 (Suppl 58) P2359;

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MicroRNA-155 controls pulmonary artery fibroblast cell signalling and proliferation in a knockout mouse model: A role in pulmonary arterial hypertension
Neil McGlinchey, Connor Bradley, Charles McSharry, Andrew Peacock, David Welsh
European Respiratory Journal Sep 2014, 44 (Suppl 58) P2359;
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