PT  - JOURNAL ARTICLE
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
TI  - Leptin signalling system as a target for pulmonary arterial hypertension therapy
AID  - 10.1183/09031936.00193014
DP  - 2015 Apr 01
TA  - European Respiratory Journal
PG  - 1066--1080
VI  - 45
IP  - 4
4099  - http://erj.ersjournals.com/content/45/4/1066.short
4100  - http://erj.ersjournals.com/content/45/4/1066.full
SO  - Eur Respir J2015 Apr 01; 45
AB  - 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 PH 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-induced 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