Local and Systemic RAGE Axis Changes in Pulmonary Hypertension: CTEPH and iPAH

PLOS ONE, Dec 2019

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.

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Local and Systemic RAGE Axis Changes in Pulmonary Hypertension: CTEPH and iPAH

et al. (2014) Local and Systemic RAGE Axis Changes in Pulmonary Hypertension: CTEPH and iPAH. PLoS ONE 9(9): e106440. doi:10.1371/journal.pone.0106440 Local and Systemic RAGE Axis Changes in Pulmonary Hypertension: CTEPH and iPAH Bernhard Moser 0 Anna Megerle 0 Christine Bekos 0 Stefan Janik 0 Tama s Szerafin 0 Peter Birner 0 Ana- Iris Schiefer 0 Michael Mildner 0 Irene Lang 0 Nika Skoro-Sajer 0 Roela Sadushi-Kolici 0 Shahrokh Taghavi 0 Walter Klepetko 0 Hendrik Jan Ankersmit 0 James West, Vanderbilt University Medical Center, United States of America 0 1 Department of Thoracic Surgery, Division of Surgery, Medical University Vienna , Vienna , Austria , 2 Christian Doppler Laboratory for the Diagnosis and Regeneration of Cardiac and Thoracic Diseases, Medical University Vienna , Vienna , Austria , 3 Department of Cardiac Surgery, University of Debrecen, Debrecen, Hungary, 4 Department of Pathology, Medical University Vienna , Vienna , Austria , 5 Department of Dermatology, Medical University Vienna , Vienna , Austria , 6 Department of Internal Medicine II, Division of Cardiology, Medical University Vienna , Vienna , Austria 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 (aSMA+vimentin+CD342), 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. - 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. Competing Interests: The authors have declared that no competing interests exist. Pulmonary hypertension (PH) is currently defined as a hemodynamic and pathophysiological condition with a mean pulmonary artery pressure (PAPmean) of $25 mmHg at rest. The European Society of Cardiology (ESC) and European Respiratory Society (ERS) have classified these conditions into six groups. Pulmonary arterial hypertension (PAH, group 1) can be the result of a wide array of underlying diseases. The entity idiopathic pulmonary arterial hypertension (iPAH, group 1.1) is used if no underlying causative disease can be diagnosed. The increase in pulmonary vascular resistance (PVR) is related to different mechanisms, including vasoconstriction, proliferative and obstructive remodeling of the pulmonary vessel wall, inflammation and thrombosis. The pathology of idiopathic pulmonary arterial hypertension affects the small distal pulmonary arteries (PAs) with a diameter less than 500 mm. Typical findings are hypertrophy of the media, intimal proliferative and fibrotic changes, thickening of the adventitia with perivascular inflammatory infiltrates, complex Figure 1. RAGE and HMGB1 are expressed in myofibroblasts of endarterectomised chronic thromboembolic tissue (...truncated)


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Bernhard Moser, Anna Megerle, Christine Bekos, Stefan Janik, Tamás Szerafin, Peter Birner, Ana-Iris Schiefer, Michael Mildner, Irene Lang, Nika Skoro-Sajer, Roela Sadushi-Kolici, Shahrokh Taghavi, Walter Klepetko, Hendrik Jan Ankersmit. Local and Systemic RAGE Axis Changes in Pulmonary Hypertension: CTEPH and iPAH, PLOS ONE, 2014, Volume 9, Issue 9, DOI: 10.1371/journal.pone.0106440