Abstract 12206: Endothelial-derived Mif Contributes to Pulmonary Endothelial Cell Proliferation in Human Pulmonary Arterial Hypertension

Abstract

Introduction: 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. Hypothesis: We therefore hypothesized that MIF could function as a growth/survival factor promoting the altered P-EC phenotype in iPAH and disease progression. Methods: We examined the expression and the role of MIF in human lung tissues and in cultured pulmonary endothelial cells of control and idiopathic patients. In addition, two complementary animal models of pulmonary hypertension (PH) have been studied: the monocrotaline (MCT) and SU5416 plus chronic hypoxia (SuHx) rat models. 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 two experimental models of PH. These in situ observations were replicated in vitro , with cultures 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 and apoptosis-resistant phenotype of iPAH endothelial cells.