Abstract
Impaired regulatory T lymphocytes (Treg) in pulmonary arterial hypertension (PAH) could be influenced by excessive pulmonary endothelial (P-EC)-derived leptin, a HIF-1α-dependent gene (Huertas, A. et al. Eur Respir J 2012; 40:895-904). However, the significance of the HIF/leptin/leptin receptor (ObR) axis for PAH susceptibility and/or progression remains unexplored.
Hence, we hypothesized that modulating this axis could reduce the susceptibility/progression of pulmonary hypertension (PH) and protect against Treg impairment.
Herein, we used two in vivo strategies in a rat hypoxic PH model: a curative treatment with dichloroacetate (DCA; a HIF-1α inhibitor) and ObR-deficient rats (ZDF). DCA-treated and ZDF rats developed less severe PH, with lower hemodynamics at right heart catheterization, decreased percentage of pulmonary muscularized arteries and in situ inflammation, compared to untreated and wild type rats, respectively. Moreover, Treg function from DCA-treated and ZDF rats was less impaired in hypoxia, as measured by their leptin signaling pathway activation state (pSTAT3) and by their secretion levels of IL-10 and TGF-β. Importantly, we showed a time-dependent leptin-induced Treg impairment and its reversibility using a soluble leptin neutralizer. Finally, cultured human P-ECs incubated with DCA secreted less leptin, suggesting DCA efficacy in Treg protection.
We are demonstrating for the first time that the HIF/leptin/ObR axis contributes to PH susceptibility/progression, possibly through Treg impairment, highlighting the crucial role of P-EC dysfunction and autoimmunity crosstalk in PAH. This crosstalk may represent a new therapeutical target.
- © 2014 ERS