title: Local and systemic RAGE axis changes in pulmonary hypertension: CTEPH and iPAH.
abstract: OBJECTIVE
  The molecular determinants of chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) remain poorly understood. The receptor for advanced glycation endproducts (RAGE) and its ligands: HMGB1 and S100A9 are involved in inflammatory disorders. We sought to investigate the role of the RAGE axis in patients with CTEPH undergoing pulmonary endarterectomy (PEA), iPAH undergoing lung transplantation (LuTX). The high pulmonary vascular resistance in CTEPH/iPAH results in pressure overload of the right ventricle. We compared sRAGE measurements to that of patients with aortic valve stenosis (AVS) - pressure overload of the left ventricle.
  
  
  METHODS
  We enrolled patients with CTEPH(26), iPAH(15), AVS(15) and volunteers(33). Immunohistochemistry with antibodies to RAGE and HMGB1 was performed on PEA specimens and lung tissues. We employed enzyme-linked immunosorbent assays to determine the concentrations of sRAGE, esRAGE, HMGB1 and S100A9 in serum of volunteers and patients with CTEPH, iPAH, AVS before and after PEA, LuTX and aortic valve replacement (AVR).
  
  
  RESULTS
  In endarterectomised tissues from patients with CTEPH RAGE and HMGB1 were identified in myofibroblasts (α-SMA+vimentin+CD34-), recanalizing vessel-like structures of distal myofibrotic tissues and endothelium of neointima. RAGE was differentially expressed in prototypical Heath Edwards lesions in iPAH. We found significantly increased serum concentrations of sRAGE, esRAGE and HMGB1 in CTEPH. In iPAH, sRAGE and esRAGE were significantly higher than in controls. Serum concentrations of sRAGE were significantly elevated in iPAH(p<0.001) and CTEPH(p = 0.001) compared to AVS. Serum sRAGE was significantly higher in iPAH compared to CTEPH(p = 0.042) and significantly reduced in AVS compared to controls(p = 0.001). There were no significant differences in sRAGE serum concentrations before and after surgical therapy for CTEPH, iPAH or AVS.
  
  
  CONCLUSIONS
  Our data suggest a role for the RAGE pathway in the pathophysiology of CTEPH and iPAH. PEA improves the local control of disease but may not influence the systemic inflammatory mechanisms in CTEPH patients through the RAGE pathway.
authors.affiliation: Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Moser
authors.affiliation: Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Megerle
authors.affiliation: Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for the Diagnosis and Regeneration of Cardiac and Thoracic Diseases, Medical University Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Bekos
authors.affiliation: Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Janik
authors.affiliation: Department of Cardiac Surgery, University of Debrecen, Debrecen, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Szerafin
authors.affiliation: Department of Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.affiliation: Department of Pathology, Medical University Vienna, Vienna, Austria.
authors.forename: Ana-Iris
authors.initials: AI
authors.lastname: Schiefer
authors.affiliation: Department of Dermatology, Medical University Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Mildner
authors.affiliation: Department of Internal Medicine II, Division of Cardiology, Medical University Vienna, Vienna, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Lang
authors.affiliation: Department of Internal Medicine II, Division of Cardiology, Medical University Vienna, Vienna, Austria.
authors.forename: Nika
authors.initials: N
authors.lastname: Skoro-Sajer
authors.affiliation: Department of Internal Medicine II, Division of Cardiology, Medical University Vienna, Vienna, Austria.
authors.forename: Roela
authors.initials: R
authors.lastname: Sadushi-Kolici
authors.affiliation: Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: Shahrokh
authors.initials: S
authors.lastname: Taghavi
authors.affiliation: Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: Department of Thoracic Surgery, Division of Surgery, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for the Diagnosis and Regeneration of Cardiac and Thoracic Diseases, Medical University Vienna, Vienna, Austria.
authors.forename: Hendrik Jan
authors.initials: HJ
authors.lastname: Ankersmit
mesh_terms: D000328:Adult; D000368:Aged; D001024:Aortic Valve Stenosis / Q000378:metabolism; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011655:Pulmonary Embolism / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic