Inhibition of the receptor of advanced glycation reverses pulmonary arterial hypertension

Abstract

Pulmonary arterial (PA) hypertension (PAH) is a vasculopathy characterized by enhanced PA smooth muscle cells (PASMC) proliferation and suppressed apoptosis. A recent proteomic analysis of PAH lungs demonstrated that the receptor of advanced glycation endproducts (RAGE) is one of the most upregulated proteins in PAH patients. We hypothesized that RAGE could play a critical role in PAH etiology and progression. We demonstrated a specific RAGE overexpression in PAH lungs. In human PASMC, we showed that RAGE was implicated in the proliferative and apoptosis‐resistant phenotype. Recent studies demonstrated an altered BMPR2 (Bone Morphogenetic Protein Receptor 2)/PPARγ (Peroxisome Proliferator‐Activated Receptor gamma) axis in PAH. We showed that RAGE is accountable for BMPR2/PPARγ downregulation, thus regulating proliferation and apoptosis. In vivo, RAGE inhibition (siRNA nebulization) in rats with Sugen‐induced PAH showed decreased PA pressure and right ventricular hypertrophy, associated with a significant improvement in lung perfusion and decreased PA wall thickness. To conclude, we demonstrated the implication of RAGE in PAH etiology. Thus, RAGE inhibitors, which are in clinical phase II for Alzheimer's disease, represent potential therapeutic agents for PAH treatment.A Canadian Thoracic Society scholarship to JM and Canadian Institutes of Health Research grants to SB supported this work.