Leptin signalling system as a target for pulmonary arterial hypertension therapy

Eur Respir J. 2015 Apr;45(4):1066-80. doi: 10.1183/09031936.00193014. Epub 2015 Mar 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blotting, Western
  • Case-Control Studies
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Familial Primary Pulmonary Hypertension / genetics*
  • Familial Primary Pulmonary Hypertension / physiopathology
  • Familial Primary Pulmonary Hypertension / therapy*
  • Female
  • Hemodynamics / physiology
  • Humans
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / physiopathology
  • Hypertension, Pulmonary / therapy
  • Hypoxia / physiopathology*
  • Leptin / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Molecular Targeted Therapy
  • Muscle, Smooth, Vascular / cytology
  • Myocytes, Smooth Muscle / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction / methods
  • Signal Transduction
  • Up-Regulation
  • Vascular Remodeling / genetics*


  • Leptin