RT Journal Article
SR Electronic
T1 Endothelial-derived MIF contributes to pulmonary endothelial cell proliferation in human pulmonary arterial hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA4900
DO 10.1183/13993003.congress-2015.PA4900
VO 46
IS suppl 59
A1 Le Hiress, Morane
A1 Tu, Ly
A1 Phan, Carole
A1 Thuillet, Raphaël
A1 Ricard, Nicolas
A1 Seferian, Andrei
A1 Fadel, Elie
A1 Simonneau, Gerald
A1 Huertas, Alice
A1 Tamura, Yuichi
A1 Humbert, Marc
A1 Guignabert, Christophe
YR 2015
UL http://erj.ersjournals.com/content/46/suppl_59/PA4900.abstract
AB Rationale: In idiopathic pulmonary arterial hypertension (iPAH), pulmonary-endothelial cells (P-ECs) display phenotypic abnormalities including a greater proliferative response to growth factors and apoptosis resistance; however, the precise underlying mechanisms remain obscure. Excessive MIF (macrophage migration-inhibitory factor) expression during the initial stages of tumor contributes to endothelial proliferation, tumor growth and progression.Objectives: We therefore hypothesized that MIF could function as a growth/survival factor promoting the altered P-EC phenotype in iPAH and disease progression.Results: In distal pulmonary arteries (PAs) of patients with iPAH, we found a strong immunoreactivity for MIF in the endothelium compared with PAs from control patients. This aberrant endothelial MIF expression is also found in the SU5416 plus hypoxia/normoxia- exposed rats and the monocrotaline-injected rats as models of human PAH. These in situ observations were replicated in vitro, with cultured P-ECs from patients with iPAH exhibiting increased MIF expression and release compared with control P-ECs. Decreasing MIF expression and signaling by RNA interference or a specific MIF inhibitor called ISO-1 decreased proliferation and induced apoptosis of iPAH P-ECs. Finally, we found that daily treatment of rats with ISO-1 for 2 weeks started 1 week after a subcutaneous monocrotaline injection partially reverses development of pulmonary hypertension. Conclusions: We report here that the pulmonary endothelium of iPAH patients represents a local abnormal source of MIF that could contribute to the hyperproliferative phenotype of iPAH endothelial cells.