RT Journal Article
SR Electronic
T1 LSC 2014 abstract - Inhibition of the HIF/leptin/ObR axis prevents experimental pulmonary hypertension and attenuates treg impairment
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2945
VO 44
IS Suppl 58
A1 Alice Huertas
A1 Ly Tu
A1 Morane Le Hiress
A1 Nicolas Ricard
A1 Raphaël Thuillet
A1 Carole Phan
A1 Marc Humbert
A1 Christophe Guignabert
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/2945.abstract
AB 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.