Eur Respir J. 2015 Apr;45(4):1066-80.

Eur Respir J. 2015 Apr;45(4):1066-80. doi: 10.1183/09031936.00193014. Epub 2015 Mar 5.
Leptin signalling system as a target for pulmonary arterial hypertension therapy.
Huertas A, Tu L, Thuillet R, Le Hiress M, Phan C, Ricard N, Nadaud S, Fadel E, Humbert M, Guignabert C.

INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France AP-HP, Service de Pneumologie, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
INSERM UMR_S 956, Université Pierre and Marie Curie, Paris, France.

Abstract

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.

PMID:25745038