title: 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 (STAT3)/bone morphogenetic protein receptor 2 (BMPR2)/peroxisome proliferator-activated receptor gamma (PPARγ) in PAH. STAT3 activation induces BMPR2 downregulation, decreasing PPARγ, 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 STAT3 activator, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation, promoting PAH-PASMC proliferation and resistance to apoptosis.
  
  
  RESULTS
  In vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH-PASMC (6-fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6-fold, thus activating STAT3 and decreasing BMPR2 and PPARγ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline- and Sugen-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 Sugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR2/PPARγ axis restoration (increased by ≥60%).
  
  
  CONCLUSIONS
  We have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH.
authors.affiliation: Pulmonary Hypertension Group of the Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Quebec City, Canada.
authors.forename: Jolyane
authors.initials: J
authors.lastname: Meloche
authors.forename: Antony
authors.initials: A
authors.lastname: Courchesne
authors.forename: Marjorie
authors.initials: M
authors.lastname: Barrier
authors.forename: Sophie
authors.initials: S
authors.lastname: Carter
authors.forename: Malik
authors.initials: M
authors.lastname: Bisserier
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lauzon-Joset
authors.forename: Sandra
authors.initials: S
authors.lastname: Breuils-Bonnet
authors.forename: Éve
authors.initials: É
authors.lastname: Tremblay
authors.forename: Sabrina
authors.initials: S
authors.lastname: Biardel
authors.forename: Christine
authors.initials: C
authors.lastname: Racine
authors.forename: Christian
authors.initials: C
authors.lastname: Courture
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonnet
authors.forename: Susan M
authors.initials: SM
authors.lastname: Majka
authors.forename: Yves
authors.initials: Y
authors.lastname: Deshaies
authors.forename: Frédéric
authors.initials: F
authors.lastname: Picard
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D062186:Arterial Pressure; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications; D007211:Indoles; D008297:Male; D008875:Middle Aged; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism; D011758:Pyrroles; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009418:S100 Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
chemical_list: D017127:Glycation End Products, Advanced; D007211:Indoles; D047495:PPAR gamma; D011758:Pyrroles; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; C116890:Semaxinib; D016686:Monocrotaline; C498218:BMPR2 protein, human; C498220:Bmpr2 protein, rat; D052006:Bone Morphogenetic Protein Receptors, Type II