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

Suzuki, Satoshi; Nakazato, Kazuhiko; Sugimoto, Koichi; Yoshihisa, Akiomi; Yamaki, Takashi; Kunii, Hiroyuki; Suzuki, Hitoshi; Saitoh, Shu‐ichi; Takeishi, Yasuchika

doi:10.1536/ihj.15-188

Cited by 22 publications

(23 citation statements)

References 26 publications

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“…Several investigators have reported that expression levels of RAGE were increased in serum or plasma, small pulmonary arteries and PASMCs of patients with PAH [9, 19, 20]. Here, we showed that RAGE was overexpressed in PASMCs of not only patients with IPAH but also patients with HPAH including patients with BMPR2 mutation and SMAD9 mutation.…”

Section: Discussionsupporting

confidence: 58%

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

et al. 2018

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BackgroundPulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH.Methods and resultsPASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001).ConclusionsRAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

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Section: Discussionsupporting

confidence: 58%

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

et al. 2018

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“…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.…”

Section: Article P234mentioning

confidence: 95%

“…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.…”

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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“…Several biochemical markers for PH have been explored, but a specific marker has not been established. [3][4][5] Right heart catheterization (RHC) is required for the definitive diagnosis of PH (mean pulmonary arterial pressure (MPAP) !25 mmHg at rest); 6) however, RHC is inappropriate for screening because of its invasiveness.…”

mentioning

confidence: 99%

Deeper S Wave in Lead V5 and Broader Extent of T Wave Inversions in the Precordial Leads are Clinically Useful Electrocardiographic Parameters for Predicting Pulmonary Hypertension

et al. 2018

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SummaryElectrocardiography (ECG) is used to screen for pulmonary hypertension (PH). However, it is unclear which parameters of ECG are the most useful for screening.ECG parameters related to right ventricular hypertrophy criteria were examined in 145 ECGs of subjects who were suspected to have PH and underwent right heart catheterization (RHC) (age 58.4 ± 17.5 years, 112 women, mean pulmonary arterial pressure [MPAP] 35.4 ± 13.3 mmHg). Based on the results of RHC, 108 subjects had PH (56 pulmonary arterial hypertension [PAH] and 52 chronic thromboembolic pulmonary hypertension [CTEPH]).Fourteen of 17 ECG parameters in the present study were significantly associated with PH on univariate analysis. On multivariable logistic regression analysis, S wave depth in lead V5 (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.10-1.47) and depth of T wave inversion in lead V4 (OR 1.21, 95% CI 1.03-1.46) were independent predictors of MPAP !25 mmHg, and the cut-off values determined by receiver operating characteristic curve analyses were 0.42 mV and -0.28 mV, respectively.In conclusion, a deeper S wave in lead V5 and the presence of a wider extent of negative T waves in the precordial leads may be clinically simple and useful ECG parameters for screening for PH.(Int Heart J 2018; 59: 136-142) Key words: Pulmonary arterial hypertension, Chronic thromboembolic pulmonary hypertension P ulmonary hypertension (PH) causes pressure overload of the right ventricle (RV) with RV hypertrophy and dilatation, leading to right heart failure and premature death. Despite recent advances in management, the prognosis of PH patients is still poor, with a 3-year survival rate of 67%.

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

Cited by 22 publications

References 26 publications

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

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

Deeper S Wave in Lead V5 and Broader Extent of T Wave Inversions in the Precordial Leads are Clinically Useful Electrocardiographic Parameters for Predicting Pulmonary Hypertension

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