RT Journal Article
SR Electronic
T1 Elucidating signalling pathways in pulmonary hypertension using a microRNA knockout mouse model – In vitro and in vivo data
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA592
DO 10.1183/13993003.congress-2015.PA592
VO 46
IS suppl 59
A1 McGlinchey, Neil
A1 Samillan, Victor
A1 Kurowska-Stolarska, Mariola
A1 McSharry, Charles
A1 Nilsen, Margaret
A1 MacLean, Mandy
A1 Peacock, Andrew
A1 Welsh, David
YR 2015
UL http://erj.ersjournals.com/content/46/suppl_59/PA592.abstract
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.