Local and systemic RAGE axis changes in pulmonary hypertension: CTEPH and iPAH

PLoS One. 2014 Sep 4;9(9):e106440. doi: 10.1371/journal.pone.0106440. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aortic Valve Stenosis / metabolism
  • Female
  • Humans
  • Hypertension, Pulmonary / metabolism*
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Prospective Studies
  • Pulmonary Embolism / metabolism*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism*

Substances

  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic

Grants and funding

The study was funded by the Research laboratories of the Department of Surgery (FOLAB ARGE Moser) of the Medical University Vienna and the Christian Doppler laboratory for the Diagnosis and Regeneration of Cardiac and Thoracic Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.