TY - JOUR T1 - Leptin signalling system as a target for pulmonary arterial hypertension therapy JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/09031936.00193014 SP - ERJ-01930-2014 AU - Alice Huertas AU - Ly Tu AU - Raphaël Thuillet AU - Morane Le Hiress AU - Carole Phan AU - Nicolas Ricard AU - Sophie Nadaud AU - Elie Fadel AU - Marc Humbert AU - Christophe Guignabert Y1 - 2015/03/05 UR - http://erj.ersjournals.com/content/early/2015/03/05/09031936.00193014.1.abstract N2 - Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH. In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ⩽5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to pulmonary hypertension susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-hypertension PH. We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH. Targeting Ob/ObR-b axis represents an important tool for anti-proliferative and anti-inflammatory strategies in PH http://ow.ly/I00jh ER -