Critical Role for the Advanced Glycation End‐Products Receptor in Pulmonary Arterial Hypertension Etiology

Abstract

Background: Pulmonary arterial hypertension ( PAH ) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell ( PASMC ) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 ( STAT 3)/bone morphogenetic protein receptor 2 ( BMPR 2)/peroxisome proliferator‐activated receptor gamma ( PPAR γ) in PAH . STAT 3 activation induces BMPR 2 downregulation, decreasing PPAR γ, which both contribute to the proproliferative and antiapoptotic phenotype seen in PAH . In chondrocytes, activation of this axis has been attributed to the advanced glycation end‐products receptor ( RAGE ). As RAGE is one of the most upregulated proteins in PAH patients' lungs and a strong STAT 3 activator, we hypothesized that by activating STAT 3, RAGE induces BMPR 2 and PPAR γ downregulation, promoting PAH ‐ PASMC proliferation and resistance to apoptosis. Methods and Results: In vitro, using PASMC s isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH ‐ PASMC (6‐fold increase), thus inducing STAT 3 activation (from 10% to 40% positive cells) and decrease in BMPR 2 and PPAR γ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6‐fold, thus activating STAT 3 and decreasing BMPR 2 and PPAR γ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline‐ and S ugen‐induced PAH demonstrates therapeutic effects characterized by PA pressure and right ventricular hypertrophy decrease (control rats have an mPAP around 15 mm Hg, PAH rats have an mPAP >40 mm Hg, and with RAGE inhibition, mPAP decreases to 20 and 28 mm Hg, respectively, in MCT and S ugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR 2/ PPAR γ axis restoration (increased by ≥60%). Conclusion: We have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH .