RT Journal Article
SR Electronic
T1 Leptin signalling system as a target for pulmonary arterial hypertension therapy
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1066
OP 1080
DO 10.1183/09031936.00193014
VO 45
IS 4
A1 Alice Huertas
A1 Ly Tu
A1 Raphaël Thuillet
A1 Morane Le Hiress
A1 Carole Phan
A1 Nicolas Ricard
A1 Sophie Nadaud
A1 Elie Fadel
A1 Marc Humbert
A1 Christophe Guignabert
YR 2015
UL http://erj.ersjournals.com/content/45/4/1066.abstract
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