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

Moser, Bernhard; Megerle, Anna; Bekos, Christine; Janik, Stefan; Szerafin, Tamás; Birner, Peter; Schiefer, Ana‐Iris; Mildner, Michael; Lang, Irene M.; Skoro-Sajer, Nika; Sadushi-Koliçi, Roela; Taghavi, Shahrokh; Klepetko, Walter; Ankersmit, Hendrik Jan

doi:10.1371/journal.pone.0106440

Cited by 26 publications

(26 citation statements)

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“…25) From their report and our results, the essential role of HMGB1 and soluble RAGE might be different between idiopathic PAH and CTEPH patients. Few reports have demonstrated an association between RAGE, HMGB1 and CTEPH, therefore, the role of HMGB 1 and soluble RAGE in CTEPH patients might be an important research target in the future.…”

Section: Discussionmentioning

confidence: 53%

Plasma Levels of Receptor for Advanced Glycation End-Products and High-Mobility Group Box 1 in Patients With Pulmonary Hypertension

et al. 2016

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SummaryAn increase of pulmonary artery pressure in patients with pulmonary hypertension (PH) results in right ventricular failure and ultimately death. High-mobility group box 1 (HMGB1), a nuclear protein, acts as a pro-inflammatory cytokine by activating receptor for advanced glycation end-products (RAGE) in the extracellular environment. The purpose of this study was to examine the clinical significance of circulating levels of HMGB1 and RAGE in patients with PH. Plasma levels of HMGB1 and soluble RAGE were measured in 27 patients with PH (14 with pulmonary arterial hypertension [PAH], 13 with chronic thromboembolic pulmonary hypertension [CTEPH]) and 30 normal subjects as control. There was no difference in the plasma levels of HMGB1 between the PH patients and the control subjects. However, plasma levels of soluble RAGE were significantly higher in the patients with PH than in the controls (P < 0.001). Plasma soluble RAGE levels were higher in PAH (P < 0.001) and CTEPH (P < 0.0001) than in the controls. In addition, there was a statistically significant positive correlation between pulmonary artery pressure and plasma levels of soluble RAGE (r = 0.403, P < 0.0001). In the CTEPH patients, soluble RAGE levels were reduced after balloon pulmonary angioplasty (P < 0.001). Plasma levels of soluble RAGE, but not HMGB1, might be a novel marker that reflects the pathological condition in patients with PH. (Int Heart J 2016; 57: 234-240)

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Section: Discussionmentioning

confidence: 53%

Plasma Levels of Receptor for Advanced Glycation End-Products and High-Mobility Group Box 1 in Patients With Pulmonary Hypertension

et al. 2016

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“…15 Endarterectomized tissues from patients with CTEPH show vessel-like structures in material obtained from distal areas, whereas proximal material is characterized by lower cell density and sometimes the accumulation of fresh thrombotic material. 16 In this study, we aimed to establish whether NET formation is a feature of vascular pathology in CTEPH and PAH, study the effects of NETs on pulmonary endothelial and smooth muscle responses in vitro, and investigate the signaling mechanisms involved. We are the first to document NET formation in CTEPH and PAH and show that NETs trigger inflammatory activation of pulmonary endothelial cells and promote endothelial angiogenesis in vitro and in vivo via myeloperoxidase/ H 2 O 2 /nuclear factor κB (NFκB)/TLR4-dependent signaling.…”

mentioning

confidence: 99%

Neutrophil Extracellular Traps Promote Angiogenesis

Aldabbous

Abdul-Salam

McKinnon

et al. 2016

ATVB

173

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Objective— Inflammation and dysregulated angiogenesis are features of endothelial dysfunction in pulmonary hypertension. Neutrophil extracellular traps (NETs), produced by dying neutrophils, contribute to pathogenesis of numerous vascular disorders but their role in pulmonary hypertension has not been studied. We sought evidence of (NETs) formation in pulmonary hypertension and investigated the effect of NETs on endothelial function. Approach and Results— Plasma and lung tissues of patients with pulmonary hypertension were analyzed for NET markers. The effects of NETs on endothelial function were studied in vitro and in vivo. Patients with chronic thromboembolic pulmonary hypertension and idiopathic pulmonary hypertension showed elevated plasma levels of DNA, neutrophil elastase, and myeloperoxidase. NET-forming neutrophils and extensive areas of NETosis were found in the occlusive plexiform lesions and vascularized intrapulmonary thrombi. NETs induced nuclear factor κB–dependent endothelial angiogenesis in vitro and increased vascularization of matrigel plugs in vivo. Angiogenic responses were associated with increased release of matrix metalloproteinase-9, heparin-binding epidermal growth factor–like growth factor, latency-associated peptide of the transforming growth factor β1, and urokinase-type plasminogen activator, accompanied by increased endothelial permeability and cell motility. NETs-induced responses depended on myeloperoxidase/H 2 O 2 -dependent activation of Toll-like receptor 4/nuclear factor κB signaling. NETs stimulated the release of endothelin-1 in HPAECs (human pulmonary artery endothelial cells) and stimulated pulmonary smooth muscle cell proliferation in vitro. Conclusions— We are the first to implicate NETs in angiogenesis and provide a functional link between NETs and inflammatory angiogenesis in vitro and in vivo. We demonstrate the potential pathological relevance of this in 2 diseases of disordered vascular homeostasis, pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

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“…Moser, et al actually demonstrated that there were no significant differences in sRAGE levels before and after pulmonary endarterectomy. 8) They reported similar findings in patients with IPAH who underwent lung transplantation. This discrepancy may be partly attributed to the properties of RAGE that have multiple ligands.…”

Section: Article P234mentioning

confidence: 65%

“…7) Moser, et al also reported that sRAGE levels were significantly higher in patients with idiopathic PAH (IPAH) and CTEPH than in controls. 8) On the other hand, they elucidated that significant elevation of HMGB1 was observed in patients with CTEPH but was not observed in patients with IPAH. Suzuki, et al also demonstrated that sRAGE levels had significant correlation with tricuspid valvular regurgitation pressure gradient (TRPG) while HMGB1 levels did not have significant correlation with TRPG.…”

Section: Article P234mentioning

confidence: 99%

Potential of Receptor for Advanced Glycation End-Products (RAGE) as an Eligible Biomarker for Therapy Evaluation in Patients With Pulmonary Hypertension

Hatano

2016

Int. Heart J.

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H igh-mobility group box 1 (HMGB1) is secreted by activated macrophages and monocytes and acts as a cytokine mediator of inflammation. HMGB1 is one of the ligands of receptor for advanced glycation end-products (RAGE). Activation of RAGE induces vascular injury through the release of pro-inflammatory cytokines. Recently, both HMGB1 and RAGE were reported to be associated with the development of pulmonary arterial hypertension (PAH). [1][2][3][4][5] RAGE is recognized as a pattern-recognition receptor and able to bind multiple ligand such as AGE and S100A4 other than HMGB1.6) The clinical significance of circulating levels of HMGB1 and RAGE in patients with pulmonary hypertension (PH) seems to differ because the impact of RAGE on PH is influenced by not only HMGB1 but also other ligands. Furthermore, little is known about the association between HMGB1 or RAGE and other etiologies of PH such as chronic thromboembolic pulmonary hypertension (CTEPH). Article p.234Suzuki, et al demonstrated that plasma soluble RAGE (sRAGE) levels were significantly higher in patients with PAH and CTEPH than in controls, but there was no significant difference in the plasma levels of HMGB1 between patients with PH and controls. 7) Moser, et al also reported that sRAGE levels were significantly higher in patients with idiopathic PAH (IPAH) and CTEPH than in controls.8) On the other hand, they elucidated that significant elevation of HMGB1 was observed in patients with CTEPH but was not observed in patients with IPAH. Suzuki, et al also demonstrated that sRAGE levels had significant correlation with tricuspid valvular regurgitation pressure gradient (TRPG) while HMGB1 levels did not have significant correlation with TRPG. 7) From these findings, sRAGE is considered to be a more sensitive marker of PH than HMGB1 and may reflect the severity of PH. In fact, Suzuki, et al demonstrated that sRAGE was immediately decreased after balloon pulmonary angioplasty (BPA) in patients with CTEPH. However, hemodynamic status usually did not improve soon after BPA and Suzuki, et al indicated that the changes in pulmonary arterial pressure before and after BPA were not correlated with sRAGE. CTEPH is not just a regional disease but may derive from multiple systemic disorders such as inflammation, immune abnormality, and malignancy. Given such a background, the elevation of sRAGE in patients with CTEPH might reflect systemic abnormality and topical treatment might not lead to a reduction in sRAGE. Moser, et al actually demonstrated that there were no significant differences in sRAGE levels before and after pulmonary endarterectomy. 8) They reported similar findings in patients with IPAH who underwent lung transplantation. This discrepancy may be partly attributed to the properties of RAGE that have multiple ligands. In fact, S100A4, another ligand for RAGE, was implicated to also have important roles in PAH progression.9,10) The reduction of sRAGE after BPA in this study may come from interactions with ligands other than HMGB1. Therefore, further investi...

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

Cited by 26 publications

References 67 publications

Plasma Levels of Receptor for Advanced Glycation End-Products and High-Mobility Group Box 1 in Patients With Pulmonary Hypertension

Plasma Levels of Receptor for Advanced Glycation End-Products and High-Mobility Group Box 1 in Patients With Pulmonary Hypertension

Neutrophil Extracellular Traps Promote Angiogenesis

Potential of Receptor for Advanced Glycation End-Products (RAGE) as an Eligible Biomarker for Therapy Evaluation in Patients With Pulmonary Hypertension

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