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.
Abstract
Targeting Ob/ObR-b axis represents an important tool for anti-proliferative and anti-inflammatory strategies in PH http://ow.ly/I00jh
Footnotes
This article has supplementary material available from erj.ersjournals.com
Support statement: This research was supported by grants from the French National Institute for Health and Medical Research (INSERM, the French National Agency for Research: grant ANR_12_JSV1_0004_01), from GlaxoSmithKline (PAH grant 2013), and from Pfizer (IIR grant WI182054). Funding information for this article has been deposited with FundRef
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received October 17, 2014.
- Accepted January 19, 2015.
- Copyright ©ERS 2015