The Role Of RAGE-mediated Extracellular Matrix Proteins Accumulation In The Development Of Pulmonary Hypertension

Background: Extracellular matrix(ECM)proteins accumulation contributes to the progression of pulmonary arterial hypertension(PAH),a dangerous cardiovascular condition defined by high pulmonary arterial pressure and pulmonary vascular remodeling.Current therapies fail to fully reverse vascular remodeling and improve long-term survival.Therefore,discovery of new molecular targets or signaling pathways therapeutically capable of inhibiting remodeling of pulmonary arteries is urgently needed.The receptor for advanced glycation end products(RAGE)is constitutively expressed in the lung and plays a important role in deposition of ECM.Nonetheless,the mechanisms by which RAGE mediates ECM deposition/formation in pulmonary arteries and its roles in PAH progression are unclear.Methods and results: The expression levels of RAGE and two of its signal transducing ligands,S100/calgranulins and high mobility group box 1(HMGB-1),were increased in human and mouse pulmonary arterial smooth muscles(PASMCs)under hypoxic conditions and were strikingly upregulated in pulmonary arteries in hypoxia plus SU5416(Hy Su)-induced PAH in mice.Moreover,the blockade of RAGE by antibodies in human PASMCs exposed to hypoxia or in homozygous RAGE null mice subjected to Hy Su suppressed the expression of fibrotic proteins by reducing TGF-β1 expression.RAGE expression in RAGE-deficient mouse PASMCs restored hypoxia-stimulated TGF-β1 production via the activation of the ERK1/2 and p38 MAPK pathways and the accumulation of ECM proteins.Interaction between RAGE and HMGB1 but not toll-like receptor 4(TLR4)mediated deposition of ECM in PASMCs.Additionally,in both idiopathic PAH patients and Hy Su-induced PAH mice,the serum concentrations of soluble RAGE(s RAGE)and two of RAGE’s ligands,S100 B and HMGB1,were significantly elevated compared to controls and correlated with severity of PAH.Conclusions: The activation of the RAGE axis exacerbates pulmonary vascular remodeling and promotes the development of pulmonary hypertension.Our results indicate that s RAGE is a potential biomarker for the diagnosis of PAH and evaluation of disease severity.Furthermore,RAGE is logical target for PAH treatment.