scholarly journals Critical Role for the Advanced Glycation End‐Products Receptor in Pulmonary Arterial Hypertension Etiology

2013 ◽  
Vol 2 (1) ◽  
Author(s):  
Jolyane Meloche ◽  
Antony Courchesne ◽  
Marjorie Barrier ◽  
Sophie Carter ◽  
Malik Bisserier ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Advanced Glycation End Products ◽  
Critical Role ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Pulmonary Arterial

scholarly journals Soluble Receptor for Advanced Glycation End Products (sRAGE) Is a Sensitive Biomarker in Human Pulmonary Arterial Hypertension

2021 ◽  
Vol 22 (16) ◽  
pp. 8591
Author(s):  
Franziska Diekmann ◽  
Philippe Chouvarine ◽  
Hannes Sallmon ◽  
Louisa Meyer-Kobbe ◽  
Moritz Kieslich ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Advanced Glycation End Products ◽  
Unmet Need ◽  
Advanced Glycation ◽  
Characteristic Analysis ◽  
Soluble Rage ◽  
Glycation End Products ◽  
End Products ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive condition with an unmet need for early diagnosis, better monitoring, and risk stratification. The receptor for advanced glycation end products (RAGE) is activated in response to hypoxia and vascular injury, and is associated with inflammation, cell proliferation and migration in PAH. For the adult cohort, we recruited 120 patients with PAH, 83 with idiopathic PAH (IPAH) and 37 with connective tissue disease-associated PAH (CTD-PAH), and 48 controls, and determined potential plasma biomarkers by enzyme-linked immunoassay. The established heart failure marker NTproBNP and IL-6 plasma levels were several-fold higher in both adult IPAH and CTD-PAH patients versus controls. Plasma soluble RAGE (sRAGE) was elevated in IPAH patients (3044 ± 215.2 pg/mL) and was even higher in CTD-PAH patients (3332 ± 321.6 pg/mL) versus controls (1766 ± 121.9 pg/mL; p < 0.01). All three markers were increased in WHO functional class II+III PAH versus controls (p < 0.001). Receiver-operating characteristic analysis revealed that sRAGE has diagnostic accuracy comparable to prognostic NTproBNP, and even outperforms NTproBNP in the distinction of PAH FC I from controls. Lung tissue RAGE expression was increased in IPAH versus controls (mRNA) and was located predominantly in the PA intima, media, and inflammatory cells in the perivascular space (immunohistochemistry). In the pediatric cohort, plasma sRAGE concentrations were higher than in adults, but were similar in PH (n = 10) and non-PH controls (n = 10). Taken together, in the largest adult sRAGE PAH study to date, we identify plasma sRAGE as a sensitive and accurate PAH biomarker with better performance than NTproBNP in the distinction of mild PAH from controls.

ERM protein moesin is phosphorylated by advanced glycation end products and modulates endothelial permeability

2009 ◽  
Vol 297 (1) ◽  
pp. H238-H246 ◽  
Author(s):  
Xiaohua Guo ◽  
Lingjun Wang ◽  
Bo Chen ◽  
Qiang Li ◽  
Jiping Wang ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Critical Role ◽  
Rho Kinase ◽  
Endothelial Permeability ◽  
Dominant Negative ◽  
Advanced Glycation ◽  
P38 Inhibitor ◽  
Mapk Pathways ◽  
Glycation End Products ◽  
End Products

Advanced glycation end products (AGEs) accumulated in different pathological conditions have the potent capacity to alter cellular properties that include endothelial structural and functional regulations. The disruption of endothelial barrier integrity may contribute to AGE-induced microangiopathy and macrovasculopathy. Previous studies have shown that AGEs induced the rearrangement of actin and subsequent hyperpermeability in endothelial cells (ECs). However, the mechanisms involved in this AGE-evoked EC malfunction are not well understood. This study directly evaluated the involvement of moesin phosphorylation in AGE-induced alterations and the effects of the RhoA and p38 MAPK pathways on this process. Using immortalized human dermal microvascular ECs (HMVECs), we first confirmed that the ezrin/radixin/moesin (ERM) protein moesin is required in AGE-induced F-actin rearrangement and hyperpermeability responses in ECs by knockdown of moesin protein expression with small interfering RNA. We then detected AGE-induced moesin phosphorylation by Western blot analysis. The mechanisms involved in moesin phosphorylation were analyzed by blocking AGE receptor binding and inhibiting Rho and MAPK pathways. AGE-treated HMVECs exhibited time- and dose-dependent increases in the Thr558 phosphorylation of moesin. The increased moesin phosphorylation was attenuated by preadministrations of AGE receptor antibody, Rho kinase (ROCK), or p38 inhibitor. Suppression of p38 activation via the expression of dominant negative mutants with Ad.MKK6b or Ad.p38α also decreased moesin phosphorylation. The activation of the p38 pathway by transfection of HMVECs with an adenoviral construct of dominant active MKK6b resulted in moesin phosphorylation. These results suggest a critical role of moesin phosphorylation in AGE-induced EC functional and morphological regulations. Activation of the ROCK and p38 pathways is required in moesin phosphorylation.

scholarly journals Cancer Malignancy Is Enhanced by Glyceraldehyde-Derived Advanced Glycation End-Products

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Jun-Ichi Takino ◽  
Sho-Ichi Yamagishi ◽  
Masayoshi Takeuchi
Keyword(s):  
Advanced Glycation End Products ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
A549 Cells ◽  
Migration And Invasion ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Migration Capacity ◽  
Invasion Capacity

The receptor for advanced glycation end-products (RAGEs) is associated with the malignancy of cancer. A recent study has suggested that glyceraldehyde-derived AGEs (Glycer-AGEs) enhanced the malignancy of melanoma cells, but glucose-derived AGEs did not. However, the effects of Glycer-AGEs on other cancer cells remain poorly understood, and the molecular mechanisms behind the above-mentioned effect have not been clarified. The present paper aimed to examine the effect of Glycer-AGEs on cultured lung cancer A549 cells. RAGE was expressed in A549 cells. Glycer-AGEs significantly attenuated cell proliferation. Furthermore, Glycer-AGEs enhanced the migration capacity of the cells by activating Rac1viaROS and also increased their invasion capacity. We demonstrated that Glycer-AGEs enhanced the migration and invasion of A549 cells rather than their proliferation. These results suggest that Glycer-AGEs play a critical role in the malignancy of cancer rather than its proliferation and are potential targets for therapeutic intervention.

Abstract 15460: Pulmonary Hypertension is Associated with Apoptosis, the Downregulation of S100A1, the Upregulation of S100A6 and the Receptor for Advanced Glycation end-Products

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
James Tsoporis ◽  
Vassilios Salpeas ◽  
Nikos Kavatzas ◽  
Shehla Izhar ◽  
Jean-Francois Desjardins ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Advanced Glycation End Products ◽  
Fold Increase ◽  
Left Ventricular ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Histological Evaluation ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PH), defined by a resting mean pulmonary artery pressure (PAP) >25 mm Hg, is a syndrome in which pulmonary arterial obstruction increases pulmonary vascular resistance, leading to right ventricular (RV) hypertrophy, failure, and death. Development of PH involves the complex interactions of multiple cell effectors. The possibility that the S100 calcium binding proteins S100A1, S100A6 and their receptor the receptor for advanced glycation end-products (RAGE) may be involved PH and associated apoptosis has not been tested. We examined the levels of S100A1, S100A6, S100B, RAGE and parameters of apoptosis the anti-apoptotic Bcl2 and the pro-apoptotic Bax and terminal deoxynucleotidyl transferase dUTP nick end labelling assay (TUNEL) positive nuclei in lung biopsies negative for malignancy taken by video-assisted thorascopic surgery in 6 control patients (4 male, 2 female) mean age 59.8±4.4 (SEM) years with PA>60 mmHg. S100A1 mRNA and protein as quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and histological evaluation respectively is decreased 50-60%, whereas RAGE and S100A6 mRNA and protein is increased in the whole lung predominantly in PA endothelial and smooth muscle cells approximately 4-10 fold in PH patients compared to controls. Lung S100B levels did not differ between the control and PH groups. The PH group showed a 2.1-3.5 fold increase in the whole lung BAX/BCL2 mRNA ratio and TUNEL positive nuclei compared to controls. Compared to wild type (WT), 10-12 week old S100A1-knockout mice (KO) exhibited an increased right ventricular weight as quantified by the Fulton index (WT-0.24+0.01 vs. KO-0.28+0.01, p<0.05, n=6/group), an elevation in right ventricular systolic pressures (WT-15.5+3.8 vs. KO-28.8+4.6 mmHg, p<0.05) in the absence of altered left ventricular filling pressures, a 1.5-fold increase in lung caspase-3 activity as a marker of apoptosis and 2-3 fold increase in whole lung RAGE and S100A6 mRNA expression. Our data demonstrating that absence of S100A1 results in PH describes a novel murine model of PH, which displays many of the hallmarks of the human disease, thus makes it an attractive therapeutic target in the treatment of PH.

scholarly journals S100A4 is secreted by airway smooth muscle tissues and activates inflammatory signaling pathways via receptors for advanced glycation end products

2020 ◽  
Vol 319 (1) ◽  
pp. L185-L195 ◽  
Author(s):  
Yidi Wu ◽  
Wenwu Zhang ◽  
Susan J. Gunst
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Advanced Glycation End Products ◽  
Critical Role ◽  
S100 Protein ◽  
Target Cells ◽  
Advanced Glycation ◽  
Muscle Tissues ◽  
Glycation End Products ◽  
End Products

S100A4 is a low-molecular-mass (12 kDa) EF-hand Ca2+-binding S100 protein that is expressed in a broad range of normal tissue and cell types. S100A4 can be secreted from some cells to act in an autocrine or paracrine fashion on target cells and tissues. S100A4 has been reported in the extracellular fluids of subjects with several inflammatory diseases, including asthma. Airway smooth muscle plays a critical role in airway inflammation by synthesizing and secreting inflammatory cytokines. We hypothesized that S100A4 may play an immunomodulatory role in airway smooth muscle. Trachealis smooth muscle tissues were stimulated with recombinant His-S100A4, and the effects on inflammatory responses were evaluated. S100A4 induced the activation of Akt and NF-κB and stimulated eotaxin secretion. It also increased the expression of RAGE and endogenous S100A4 in airway tissues. Stimulation of airway smooth muscle tissues with IL-13 or TNF-α induced the secretion of S100A4 from the tissues and promoted the expression of endogenous receptors for advanced glycation end products (RAGE) and S100A4. The role of RAGE in mediating the responses to S100A4A was evaluated by expressing a mutant nonfunctional RAGE (RAGEΔcyto) in tracheal muscle tissues and by treating tissues with a RAGE inhibitor. S100A4 did not activate NF-κB or Akt in tissues that were expressing RAGEΔcyto or treated with a RAGE inhibitor, indicating that S100A4 mediates its effects by acting on RAGE. Our results demonstrate that inflammatory mediators stimulate the synthesis and secretion of S100A4 in airway smooth muscle tissues and that extracellular S100A4 acts via RAGE to mediate airway smooth muscle inflammation.

scholarly journals The Trp triad within the V-domain of the receptor for advanced glycation end products modulates folding, stability and ligand binding

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Venkata S.K. Indurthi ◽  
Jaime L. Jensen ◽  
Estelle Leclerc ◽  
Sangita Sinha ◽  
Christopher L. Colbert ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Advanced Glycation End Products ◽  
Critical Role ◽  
Site Directed Mutagenesis ◽  
Tryptophan Residue ◽  
Binding Modes ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

Abstract The receptor for advanced glycation end products (RAGE) recognizes damage-associated molecular patterns (DAMPs) and plays a critical role for the innate immune response and sterile tissue inflammation. RAGE overexpression is associated with diabetic complications, neurodegenerative diseases and certain cancers. Yet, the molecular mechanism of ligand recognition by RAGE is insufficiently understood to rationalize the binding of diverse ligands. The N-terminal V-type Ig-domain of RAGE contains a triad of tryptophan residue; Trp51, Trp61 and Trp72. The role of these three Trp residues for domain folding, stability and binding of the RAGE ligand S100B was investigated through site-directed mutagenesis, UV/VIS, CD and fluorescence spectrometry, protein–protein interaction studies, and X-ray crystallography. The data show that the Trp triad stabilizes the folded V-domain by maintaining a short helix in the structure. Mutation of any Trp residue increases the structural plasticity of the domain. Residues Trp61 and Trp72 are involved in the binding of S100B, yet they are not strictly required for S100B binding. The crystal structure of the RAGE-derived peptide W72 in complex with S100B showed that Trp72 is deeply buried in a hydrophobic depression on the S100B surface. The studies suggest that multiple binding modes between RAGE and S100B exist and point toward a not previously recognized role of the Trp residues for RAGE-ligand binding. The Trp triad of the V-domain appears to be a suitable target for novel RAGE inhibitors, either in the form of monoclonal antibodies targeting this epitope, or small organic molecules.

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