Leptin signalling system as a target for pulmonary arterial hypertension therapy.
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.
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.
Alice
A
Huertas
INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Ly
L
Tu
INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Raphaël
R
Thuillet
INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Morane
M
Le Hiress
INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Carole
C
Phan
INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Nicolas
N
Ricard
INSERM UMR_S 956, Université Pierre and Marie Curie, Paris, France.
Sophie
S
Nadaud
INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Elie
E
Fadel
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.
Marc
http://orcid.org/0000-0003-0703-2892
M
Humbert
INSERM UMR_S 999, Centre Chirurgical Marie Lannelongue, LabEx LERMIT, Le Plessis-Robinson, France Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
Christophe
C
Guignabert
D000328:Adult; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D000860:Hypoxia / Q000503:physiopathology*; D020738:Leptin / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D015854:Up-Regulation; D066253:Vascular Remodeling / Q000235:genetics*
D020738:Leptin