Abstract 12046: Advanced Glycation Endproducts Receptor (RAGE): A New Therapeutic Target for Human Pulmonary Arterial Hypertension
Background: Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular remodeling. Recent studies have shown the implication of a STAT3/BMPR2 peroxisome proliferator-activated receptor gamma (PPARγ) in the etiology of PAH. Indeed the activation of STAT3 induced the downregulation of BMPR2 contributing to the decrease in PPARγ. In chondrocytes the activation of this axis has been attributed to the advanced glycation endproducts receptor (RAGE). As RAGE is one of the most upregulated protein in the PAH patients’ lungs (Abdul-Salam et al. 2010) and a strong STAT3 activator (Meloche et al. 2011), we hypothesised that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation promoting PAH-PASMC proliferation and resistance to apoptosis.
Methods/Results: In vitro, using PASMC isolated from PAH and healthy patients (n=3), we demonstrated that RAGE is overexpressed in PAH-PASMC compare to healthy PASMC. Its upregulation induces STAT3 activation decreasing BMPR2 and PPARγ (qRT-PCR; western blot). The activation of the RAGE/STAT3/BMPR2/PPARγ axis promotes PAH-PASMC proliferation (Ki67) and decreases apoptosis (TUNEL). This phenotype was totally reversed upon RAGE inhibition by siRNA. In vivo, RAGE inhibition (siRNA nebulization i.t.) in rats with monocrotaline and sugen-induced PAH shows a therapeutic effect characterized by a decrease in mean PA pressure (catheterization and Doppler); right ventricule hypertrophy (M-mode ultrasound, n=8 per group). This decrease in PAH was associated with a significant improvement in lung perfusion measured by microfil-angigram in CT-scan. This finding was confirmed post mortem by using H & E (PA wall thichkness). Decrease in PA remodeling was associated with significant decrease in both proliferation (Ki67) and resistance to apoptosis (TUNEL).
Conclusion: We demonstrated the implication of RAGE in the etiology of PAH. Moreover, we showed that RAGE constitutes a new and attractive therapeutic target for PAH. The actual development of RAGE inhibtors offers new therapeutic perspective for PAH patients.
- © 2011 by American Heart Association, Inc.