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

Abstract

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...

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

“…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.…”

Impairment of Iodine-123-Metaiodobenzylguanidine (¹²³I-MIBG) Uptake in Patients with Pulmonary Artery Hypertension

“…[5][6][7][8] Several molecules are reportedly involved in the pathophysiology of PH. [9][10][11][12] Therefore, certain biomarkers, such as asymmetric dimethylarginine, may represent pulmonary endothelial dysfunction and could be useful for early diagnosis of PH. 12) However, some biomarkers may be not specific for pulmonary endothelial function because they are also increased in patients with other systemic vascular diseases, such as arteriosclerosis.…”