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.
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.
- © 2014 ERS
