Abstract 20039: Inhibition of the HIF/Ob/ObR Axis Prevents Experimental Pulmonary Hypertension
Introduction: Dysfunctional pulmonary endothelial cells (P-ECs) from pulmonary arterial hypertension (PAH) patients secrete excessive amount of leptin (Ob), a HIF-1α-dependent gene. However, the significance of the HIF/Ob/Ob receptor (ObR) axis for PAH susceptibility and/or progression remains unexplored.
Hypothesis: Hence, we hypothesized that HIF/Ob/ObR axis may contribute to pulmonary vascular remodeling and perivascular inflammation in PAH.
Methods and Results: In human PAH lung tissues, we found a strong Ob immunostaining intensity in dysfunctional endothelium on one hand, and a marked ObR immunostaining in pulmonary smooth muscle cells (P-SMCs) on the other hand, as compared to control subjects. Consistent with our in situ observations, PAH P-ECs overproduce Ob and PAH P-SMCs overexpress ObR as compared to control cells. Interestingly, we are also demonstrating in vitro that: 1) PAH P-SMCs proliferate more in response to Ob than control cells; 2) increased Ob secretion by PAH P-ECs leads to an excessive P-SMC proliferation. Finally, we performed in vivo studies in pulmonary hypertension (PH) models to assess the role of HIF/Ob/ObR axis in both PH susceptibility, using ObR deficient rodents (ZDF), and PH progression using: (i) inductive treatment with recombinant Ob; (ii) curative treatments with either a soluble Ob neutralizer (ObR:Fc) or dichloroacetate (DCA; a HIF-1α inhibitor). After three weeks of chronic hypoxia exposure, ZDF, ObR:Fc- and DCA-treated animals developed less severe PH, as reflected by lower pulmonary hemodynamics at right heart catheterization, decreased percentage of pulmonary muscularized arteries and lower pulmonary immune infiltration, as compared to wild type or untreated animals, respectively. Interestingly, Ob-treated animals developed a more severe disease characterized by enhanced hemodynamics, increased pulmonary muscularization and perivascular inflammation.
Conclusions: We are demonstrating here, for the first time, that the HIF/Ob/ObR axis contributes to PH susceptibility and progression, highlighting the crucial role of P-EC dysfunction in their crosstalk with P-SMCs and immune cells. Inhibition of HIF/Ob/ObR axis may represent a new therapeutical target in PAH.
Author Disclosures: A. Huertas: None. L. Tu: None. R. Thuillet: None. M. Le Hiress: None. C. Phan: None. M. Humbert: None. C. Guignabert: None.
- © 2014 by American Heart Association, Inc.