PT  - JOURNAL ARTICLE
AU  - McGlinchey, Neil
AU  - Samillan, Victor
AU  - Kurowska-Stolarska, Mariola
AU  - McSharry, Charles
AU  - Nilsen, Margaret
AU  - MacLean, Mandy
AU  - Peacock, Andrew
AU  - Welsh, David
TI  - Elucidating signalling pathways in pulmonary hypertension using a microRNA knockout mouse model – In vitro and in vivo data
AID  - 10.1183/13993003.congress-2015.PA592
DP  - 2015 Sep 01
TA  - European Respiratory Journal
PG  - PA592
VI  - 46
IP  - suppl 59
4099  - http://erj.ersjournals.com/content/46/suppl_59/PA592.short
4100  - http://erj.ersjournals.com/content/46/suppl_59/PA592.full
SO  - Eur Respir J2015 Sep 01; 46
AB  - Introduction: Adventitial fibroblast proliferation, mediated by p38 mitogen-activated protein kinase (p38 MAPK), contributes to vascular remodelling in pulmonary arterial hypertension (PAH). Bone Morphogenetic Protein type-2 Receptor (BMPR2) mutations cause PAH. MicroRNA-155 over expression down regulates Smad5, a key intermediary in the BMPR pathway.Hypothesis: MicroRNA-155 down regulation influences signalling pathways relevant in the development of PAH, ameliorating the pathological phenotype in vitro and in vivo.Methods: Pulmonary adventitial fibroblasts (PAFs) were isolated from miR-155 knockout (miR-155-/-) and wild type (WT) mice. The effect of acute hypoxia on signalling pathways was assessed using Western blotting. PAF proliferation was evaluated by [3H] thymidine incorporation. WT and miR-155-/- mice were subjected to chronic hypoxia, or maintained in normal conditions. Right ventricular systolic pressure (RVSP) and RVH were measured to assess the development of pulmonary hypertension.Results: Increased Smad5 signalling was seen in miR-155-/- PAFs in normal and hypoxic conditions, compared with WT controls. Hypoxia led to enhanced p38 MAPK activity in WT PAFs, but not in miR-155-/-PAFs. WT mice developed elevated RVSP in hypoxia as expected. MiR-155-/- mice exposed to the same degree of hypoxia had significantly lower RVSP than WT controls (31.9mmHg vs 38.6mmHg; P=0.0105). A trend towards less hypoxia-induced RVH was seen in miR-155-/- mice, versus WT mice.Conclusion: Signalling pathways important in pulmonary vascular remodelling are influenced by miR-155. In vivo, this appears to partially protect against the development of pulmonary hypertension.