Abstract 14169: Crucial Role of RAGE in Inappropriate Increase of Smooth Muscle Cells From Patients With Pulmonary Arterial Hypertension
Background: Receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of inflammatory, degenerative and hyperproliferative diseases. RAGE is also implicated in etiology of pulmonary arterial hypertension (PAH) and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in PAH.
Methods and Results: PASMCs were obtained from 12 patients with PAH (including 2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining (Figure) revealed that RAGE and S100A9, a ligand of RAGE, were overexpressed in PAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE and S100A8, a ligand of RAGE, in PAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result shows overgrowth characterized by continued growth under non-growth stimulated conditions in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under non-growth stimulated conditions in PASMCs obtained from idiopathic PAH (IPAH) and hereditary PAH (HPAH) patients (P<0.0001). AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH- and HPAH-PASMCs (P<0.0001).
Conclusions: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.
Author Disclosures: K. Nakamura: None. S. Akagi: None. T. Sarashina: None. M. Sakaguchi: None. H. Matsubara: None. H. Ito: None.
- © 2016 by American Heart Association, Inc.