sRAGE Levels In Patients Research Articles

Soluble Receptor Level of Advanced Glycation (sRAGE) Products in Serum in Patients with Systemic Lupus Erythematosus:

Objectives: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by antibody formation against nuclear autoantigens. A receptor for Advanced Glycation (RAGE) is produced by many immune system cells, such as neutrophils, macrophages, and T cells, and interacts with many classes of ligands. In light of these results, the level of sRAGE, the soluble form of RAGE, may be associated with disease activity. In light of this information, we aimed to evaluate whether there is a relationship between plasma sRAGE levels and SLE. Materials and Methods: Eighteen patients diagnosed with SLE (M/F: 1/17) and twenty-one patients without any disease diagnosis (M/F: 2/19) were included as the control group. In these patients, plasma sRAGE level was measured by ELIZA method using an ELIZA (enzyme-linked immunosorbent assay) kit (BioVendor Research and Diagnostic Products). The data obtained were compared between the groups. Results: The mean plasma sRAGE level was lower in patients with SLE than in healthy control patients but not statistically significant (p=0.966). Our study found a positive correlation between SLEDAI and sRAGE levels in patients with SLE (r=0.628, p=0.005). Although no significant correlation was found between patients with SLE, sRAGE levels were positively correlated between fourteen patients classified as active SLE and the control group. Conclusions: In our study, we found that plasma sRAGE levels in patients with SLE were lower than in healthy controls, but plasma sRAGE levels in patients with active SLE were higher than plasma sRAGE levels in patients with inactive SLE. We hypothesized that reduced sRAGE levels in patients with SLE could be explained by the depletion of this soluble receptor. Our study differed from another similar study showing that blood sRAGE levels were higher in patients with SLE than in healthy controls. Blood sRAGE levels were significantly increased during active disease compared with patients with quiescent SLE.

Soluble RAGE in COPD, with or without coexisting obstructive sleep apnoea

BackgroundHypoxia can reduce the levels of soluble receptor for advanced glycation end-products (sRAGE), a new anti-inflammatory biomarker of COPD. We assessed sRAGE in patients with hypoxia-related diseases such as COPD, OSA and OSA-COPD overlap.MethodsPlasma levels of sRAGE were measured in 317 subjects at baseline (57 heathy nonsmokers [HNS], 84 healthy smokers [HS], 79 OSA, 62 COPD and 35 OSA-COPD overlap patients) and in 294 subjects after one year of follow-up (50 HNS, 74 HS, 77 OSA, 60 COPD and 33 overlap).ResultsAfter adjusting for age, sex, smoking status and body mass index, sRAGE levels showed a reduction in OSA (− 12.5%, p = 0.005), COPD (− 14.8%, p < 0.001) and OSA-COPD overlap (− 12.3%, p = 0.02) compared with HNS. There were no differences when comparing sRAGE plasma levels between overlap patients and those with OSA or COPD alone. At follow-up, sRAGE levels did not change significantly in healthy subjects, COPD and OSA or OSA-COPD overlap nontreated with continuous positive airway pressure (CPAP). Moreover, in patients with OSA and OSA-COPD overlap who were treated with CPAP, sRAGE increased significantly.ConclusionsThe levels of sRAGE are reduced in COPD and OSA. Treatment with CPAP appears to improve sRAGE levels in patients with OSA who also had COPD.

Role of the Soluble Receptor for Advanced Glycation End Products (sRAGE) as a Prognostic Factor for Mortality in Hemodialysis and Peritoneal Dialysis Patients.

End-stage renal disease patients on dialysis (CKD-G5D) have a high mortality rate due to cardiovascular diseases (CVD). In these patients, inflammation, oxidative stress, and uremia increase the production of glycation products (AGEs) which in turn accelerate CVD onset and progression. Recently, attention has been given to the soluble receptor for AGEs (sRAGE) as a marker of inflammation, oxidative stress, atherosclerosis, and heart failure in CKD-G5D. However, its association with patient outcomes is still under debate. Our aim is to explore whether sRAGE may be a predictor of mortality in CKD-G5D. We studied 123 CKD-G5D for 24 months. Of these patients, 56 were on hemodialysis (HD) and 67 on peritoneal dialysis (PD). Demographic, anthropometric, biochemical, and clinical data were recorded. sRAGE was quantified by enzyme-linked immunosorbent assay. sRAGE was a predictor of mortality at 2-year follow-up. Each increase of 100 pg/mL in sRAGE levels was associated with an approximately 7% increased risk of mortality. Furthermore, in the entire study group, as well as in PD and HD patient subgroups, sRAGE was positively correlated with brain natriuretic peptide (BNP) levels. Mortality rates as well as sRAGE levels in patients who died did not differ between PD and HD patients. In conclusion, the positive association observed with BNP levels suggests a role for sRAGE as a prognostic factor for mortality in CKD-G5D patients displaying an active process of cardiac remodeling.

Soluble Receptor for Advanced Glycation End Products (sRAGE) is Up-Regulated in Multiple Sclerosis Patients Treated with Interferon β-1a

Background/Aims: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Considering the role of immune system in its pathogenesis, researchers have focused on evaluation of the expression of immune-related genes or proteins in MS patients. Among proteins whose participation in inflammatory process has been documented is the receptor for advanced glycation end products (RAGE). Methods: In the present study, we compared RAGE transcript levels by means of quantitative real-time PCR as well as the serum level of soluble RAGE (sRAGE) by means of enzyme- linked immunosorbent assay (ELISA) in 50 IFNβ-1a responsive relapsing-remitting MS patients when compared with age and sex-matched healthy subjects. Results: Elevated expression of RAGE as well as higher levels of sRAGE were detected in IFN-β responsive MS patients compared with the controls. A significant inverse correlation between sRAGE plasma concentrations and the expanded disability status scale (EDSS) was also detected in which each unit of increase in sRAGE level resulted in a 0.308 unit decrease in EDSS. Conclusion: Considering the stable clinical state of the MS patients in this study and their response to IFNβ-1a, the elevated levels of sRAGE in patients compared with healthy subjects could be related to the effects of this kind of treatment.

Relationships between vitreous levels of soluble receptor for advanced glycation end products (sRAGE) and renal function in patients with diabetic retinopathy.

We investigated the relationship between vitreous levels of soluble receptor for advanced glycation end products (sRAGE) and vascular endothelial growth factor (VEGF) and renal function, and correlations between vitreous sRAGE levels and proliferative diabetic retinopathy (PDR) activity. We examined 33 eyes from 33 patients with diabetes mellitus who underwent a vitrectomy (eight patients in the non-PDR [NPDR] group and 25 in the PDR group). Serum creatinine levels and estimated glomerular filtration rate (eGFR) were measured and classified according to the chronic kidney disease (CKD)-staging method. Enzyme-linked immunosorbent assay (ELISA) was performed to quantify vitreous sRAGE and VEGF levels. Vitreous sRAGE levels were significantly higher in PDR group compared to NPDR group (p=0.00003). Vitreous sRAGE levels were significantly higher in patients with CKD stage 5 (end-stage renal failure or hemodialysis) than in patients with CKD stage 1 or 2 (p<0.01) and 3 or 4 (p<0.05), and were significantly correlated with eGFR (r=-0.490, p=0.007) and creatinine levels (r=0.484, p=0.006). Within the PDR group, patients with low (<27pg/mL) sRAGE levels required repeat vitreous surgeries for early postoperative vitreous hemorrhage significantly more frequently than those with high (≥27pg/mL) sRAGE levels (p=0.0067). Vitreous sRAGE levels were significantly correlated with renal function, and low vitreous sRAGE levels in patients with PDR were associated with postoperative vitreous hemorrhage. Vitreous sRAGE may be a useful biomarker for renal dysfunction associated with diabetic retinopathy.

Reduced soluble RAGE is associated with disease severity of axonal Guillain-Barré syndrome.

Soluble receptor for advanced glycation end products (sRAGE) is an anti-inflammatory factor that mitigates the proinflammatory effects of high mobility group box 1 (HMGB1). The aim of this study was to investigate whether Guillain-Barré syndrome (GBS)-related inflammation are mediated by sRAGE and HMGB1. We measured serum sRAGE, HMGB1, IL-6, and TNF-α levels in 86 patients with GBS and analysed associations between sRAGE or HMGB1 and clinical variables in these subjects. In addition, we determined cerebrospinal fluid sRAGE and HMGB1 levels in a cross-sectional study of 50 patients with GBS who had matched serum samples. We found serum sRAGE levels in patients with the acute motor axonal neuropathy (AMAN) subtype of GBS, but not other subtypes, were significantly lower than those in healthy controls, and were significantly correlated with GBS disability score and Erasmus GBS outcome score, while serum HMGB1, IL-6, and TNF-α levels in all subtypes of GBS were significantly higher than those in healthy controls. Moreover, increased sRAGE levels and decreased HMGB1 levels after treatment were observed. Our results showed that serum sRAGE may be a useful biomarker for inflammation in the AMAN GBS subtype, while HMGB1 may be related to the inflammatory process across all types of GBS.

Association between intraoperative ventilator settings and plasma levels of soluble receptor for advanced glycation end-products in patients without pre-existing lung injury.

The soluble form of the receptor for advanced glycation end-products (sRAGE) is elevated and correlated with severity in patients with acute respiratory distress syndrome (ARDS). The impact of ventilator settings on plasma levels of sRAGE, in patients with or without pre-existing lung injury, remains under-investigated to date. Our objective was to assess the effects of a lung-protective ventilation strategy (combining low tidal volume, positive end-expiratory pressure and recruitment maneuvers), as compared with a non-protective approach (with high tidal volume and zero end-expiratory pressure), on plasma levels of sRAGE in patients without lung injury undergoing major abdominal surgery. Plasma samples were obtained from 95 patients enrolled in a large randomized controlled trial of lung-protective ventilation for major abdominal surgery. Plasma levels of sRAGE were measured in duplicate with an enzyme-linked immunoassay on day 1, immediately after surgery, and on postoperative days 1, 3 and 7. Early postoperative plasma levels of sRAGE were significantly lower in the lung-protective ventilation group (n = 47) than in the non-protective ventilation group (n = 48) (mean (standard deviation), 1782 (836) vs 2171 (1678) pg/mL, respectively, P = 0.03). Intraoperative changes in plasma sRAGE were associated with postoperative hypoxemia and ARDS. A lung-protective ventilation strategy decreased plasma sRAGE in patients without lung injury undergoing major abdominal surgery compared with the patients with non-protective ventilation. This intraoperative decrease could reflect a lesser degree of epithelial injury.

Decreased levels of soluble receptor for advanced glycation end-products in aortic valve calcification patients.

The soluble receptor for advanced glycation end-products (sRAGE) shows a close relationship with atherosclerosis. The goal of this study was to compare the levels of sRAGE in patients with and without aortic valve calcification and to investigate the relationship between them. After transthoracic echocardiographic examination, 120 male patients with aortic valve calcification and 120 age-matched male controls without aortic valve calcification were included in our study. sRAGE levels were compared between groups. The prevalence of diabetes mellitus and coronary artery disease were significantly higher in the aortic valve calcification group than in the control group (63.3 versus 45%, P = 0.01, and 65 versus 51.7%, P < 0.01, respectively). The levels of sRAGE were lower in the aortic valve calcification group than in the control group (203.8 ± 34.6 versus 324.7 ± 41.6 pg/mL, P < 0.01). In multivariate analysis, age, coronary artery disease, and sRAGE levels were independent predictors of aortic valve calcification. Our study demonstrates that sRAGE, which was proven to be a potential marker of atherosclerosis, might have a role in the development of aortic valve calcification.

Low Levels of Serum Soluble Receptors for Advanced Glycation End Products, Biomarkers for Disease State: Myth or Reality

Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) on the membrane and induce deleterious effects via activation of nuclear factor kappa-B, and increased oxidative stress and inflammatory mediators. AGEs also combine with circulating soluble receptors (endogenous secretory RAGE [esRAGE] and soluble receptor for RAGE [sRAGE]) and sequester RAGE ligands and act as a cytoprotective agent. esRAGE is secreted from the cells and is a spliced variant of RAGE. The sRAGE on the other hand is proteolytically cleaved from cell surface receptor via matrix metalloproteinase (MMPs). sRAGE is elevated in type 1 and type 2 diabetes and in patients with decreased renal function. Serum levels of sRAGE are reduced in diseases including coronary artery disease, atherosclerosis, essential hypertension, chronic obstructive lung disease, heart failure, and hypercholesterolemia. Serum levels of AGEs are elevated in patients with coronary artery disease and atherosclerosis. However, the increases in serum AGEs are very high in patients with diabetes and renal disease. There is a positive correlation between serum levels of AGEs and RAGE and sRAGE. The elevated levels of sRAGE in patients with diabetes and impaired renal function may be due to increased levels of MMPs. AGEs increase in the expression and production of MMPs, which would increase the cleavage of sRAGE from cell surface. In conclusion, low level of serum sRAGE is a good biomarker for disease other than diabetes and renal disease. A unified formula that takes into consideration of AGEs, sRAGE, and esRAGE such as AGE/sRAGE or AGEs/esRAGE would be better biomarker than sRAGE or esRAGE for all AGE-RAGE-associated diseases including diabetes and renal disease.

Soluble Isoform of the Receptor for Advanced Glycation End Products as a Biomarker for Postoperative Respiratory Failure after Cardiac Surgery

PurposePostoperative respiratory failure is a major problem which can prolong the stay in the intensive care unit in patients undergoing cardiac surgery. We measured the serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE), and we studied its association with postoperative respiratory failure.MethodsEighty-seven patients undergoing elective cardiac surgery were enrolled in this multicenter observational study in three university hospitals. Serum biomarker levels were measured perioperatively, and clinical data were collected for 7 days postoperatively. The duration of mechanical ventilation was studied for 28 days.ResultsSerum levels of sRAGE elevated immediately after surgery (median, 1751 pg/mL; interquartile range (IQR) 1080–3034 pg/mL) compared with the level after anesthetic induction (median, 884 pg/mL; IQR, 568–1462 pg/mL). Postoperative sRAGE levels in patients undergoing off-pump coronary artery bypass grafting (median, 1193 pg/mL; IQR 737–1869 pg/mL) were significantly lower than in patients undergoing aortic surgery (median, 1883 pg/mL; IQR, 1406–4456 pg/mL; p = 0.0024) and valve surgery (median, 2302 pg/mL; IQR, 1447–3585 pg/mL; p = 0.0005), and postoperative sRAGE correlated moderately with duration of cardiopulmonary bypass (rs = 0.44, p<0.0001). Receiver operating characteristic curve analysis demonstrated that postoperative sRAGE had a predictive performance with area under the curve of 0.81 (95% confidence interval 0.71–0.88) for postoperative respiratory failure, defined as prolonged mechanical ventilation >3 days. The optimum cutoff value for prediction of respiratory failure was 3656 pg/mL, with sensitivity and specificity of 62% and 91%, respectively.ConclusionsSerum sRAGE levels elevated immediately after cardiac surgery, and the range of elevation was associated with the morbidity of postoperative respiratory failure. Early postoperative sRAGE levels appear to be linked to cardiopulmonary bypass, and may have predictive performance for postoperative respiratory failure; however, large-scale validation studies are needed.

AB0393 Increased in serum soluble receptor for advanced glycation end products levels are associated with improvement in augmentation index in patients with early rheumatoid arthritis- a prospective observational study

BackgroundReceptor for advanced glycation end products (RAGE) is a member of the immunoglobulin super family of cell surface molecules that is expressed in a variety of cell lines. The interaction...

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

The increased cardiovascular (CV) disease risk in patients with morbid obesity (MO) cannot be fully explained by traditional CV risk factors. Activation of the receptor of Advanced Glycation Endproducts (RAGE) leads to inflammation via the NF κβ (nuclear factor κβ) pathway. The soluble form of RAGE (sRAGE), which is present in plasma, can bind to ligands of RAGE and avoids interaction of RAGE with proinflammatory ligands. We investigated sRAGE levels in patients with MO and compared them with healthy lean controls (CO), before and after bariatric surgery. We conducted a cross-sectional study and a 24-month longitudinal study. We included 85 patients (mean age: 41 ± 12 years; mean body mass index (BMI): 45.4 ± 7.9 kg m(-2)) with MO in comparison with 40 CO (mean age: 42 ± 13 years; mean BMI: 26.0 ± 5.5 kg m(-2)). All patients were investigated before and 2 years after bariatric surgery. Apart from weight and CV risk markers (blood pressure, lipids), a glucose tolerance test (75 g), renal and inflammation parameters were assessed. sRAGE levels were assessed by a commercial ELISA. To investigate the associations of the observed reductions of values, delta (Δ) of parameters were calculated. Patients with MO had significant lower sRAGE levels than CO: 1010 ± 514 vs 1501 ± 674 pg ml(-1); P<0.001. In the longitudinal study, sRAGE levels increased significantly after bariatric surgery from 1010 ± 514 to 1261 ± 710 pg ml(-1); P=0.008. In the correlation analysis, ΔsRAGE levels were associated with Δ1-h and Δ2-h postprandial glucose, Δfasting insulin, Δ2-h postprandial insulin, ΔHOMA (homeostatic model assessment)-insulin resistance (ΔHOMA-IR), Δγ-glutamyl transferase and Δtriglycerides. In a multivariate model, Δ1-h and Δ2-h postprandial glucose, Δ2-h postprandial insulin and ΔHOMA-IR predicted ΔsRAGE. Patients with MO have significantly lower sRAGE levels compared with non-obese CO, but sRAGE levels increase significantly after weight loss induced by bariatric surgery. As high sRAGE levels inhibit the activation of inflammatory pathways, our results might help understand the beneficial effects of bariatric surgery regarding CV morbidity and mortality.

The Plasma Level of Soluble Receptor for Advanced Glycation End Products is Decreased in Patients with Systemic Lupus Erythematosus

In recent years, the role of high mobility group box-1 (HMGB1) protein and its receptors in autoimmune diseases has received increasing attention. It has been documented that HMGB1 is associated with disease activity in patients with systemic lupus erythematosus (SLE). This study was undertaken to determine the potential role of receptor for advanced glycation end products (RAGE), one receptor for HMGB1, in the pathogenesis of SLE. Plasma levels of soluble RAGE (sRAGE) from 105 patients with clinical diagnosis of SLE and 43 healthy controls were determined by ELISA. Associations between sRAGE levels and clinical, laboratory characteristics were assessed. The data showed that plasma levels of sRAGE in patients with SLE were significantly lower than those in healthy controls (HC) (P = 0.003). Plasma sRAGE in patients receiving short-period treatment showed an immediate decrease compared with the untreated patients (P = 0.023). In contrast, plasma sRAGE in patients receiving long-period treatment were significantly increased compared to those with short-period treatment (P = 0.000) and comparable with those in HC (P = 0.305). The significant decreased levels of sRAGE in patients with SLE suggest the potential association of RAGE signalling and SLE clinical pathology, whereas, long-period antilupus treatment may counteract the decreased sRAGE levels in patients with SLE.

Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis

BackgroundCommunity-acquired pneumonia (CAP) is considered the most important cause of death from infectious disease in developed countries. Severity assessment scores partially address the difficulties in identifying high-risk patients. A lack of specific and valid pathophysiologic severity markers affect early and effective sepsis therapy. HMGB-1, sRAGE and RAGE have been involved in sepsis and their potential as severity markers has been proposed. The aim of this study was to evaluate HMGB-1, RAGE and sRAGE levels in patients with CAP-associated sepsis and determine their possible association with clinical outcome.MethodWe evaluated 33 patients with CAP-associated sepsis admitted to the emergency room and followed in the medical wards. Severity assessment scores (CURB-65, PSI, APACHE II, SOFA) and serologic markers (HMGB-1, RAGE, sRAGE) were evaluated on admission.ResultsThirty patients with a diagnosis of CAP-associated sepsis were enrolled in the study within 24 hours after admission. Fourteen (46.6%) had pandemic (H1N1) influenza A virus, 2 (6.6%) had seasonal influenza A and 14 other diagnoses. Of the patients in the study group, 16 (53.3%) had a fatal outcome. ARDS was observed in 17 (56.6%) and a total of 22 patients had severe sepsis on admission (73%). The SOFA score showed the greatest difference between surviving and non-surviving groups (P = .003) with similar results in ARDS patients (P = .005). sRAGE levels tended to be higher in non-surviving (P = .058) and ARDS patients (P = .058). Logistic regression modeling demonstrated that SOFA (P = .013) and sRAGE (P = .05) were the only variables that modified the probability of a fatal outcome.ConclusionThe association of elevated sRAGE with a fatal outcome suggests that it may have an independent causal effect in CAP. SOFA scores were the only clinical factor with the ability to identify surviving and ARDS patients.

Elevated soluble receptor for advanced glycation end product levels in patients with acute coronary syndrome and positive cardiac troponin I

High levels of soluble receptor for advanced glycation end products (sRAGE) have been shown to have an atheroprotective role; however, no data are available on this molecule in acute coronary syndromes (ACS). We evaluated sRAGE levels in patients with non-ST segment elevation ACS (NSTE-ACS) or with chronic stable angina. We studied 265 patients, 190 of whom had NSTE-ACS and 75 had chronic stable angina. Plasma sRAGE values were comparable in the two groups (P=0.19). However, in the patients with NSTE-ACS, sRAGE levels were significantly higher in patients with cardiac troponin-I (cTnI) of more than or equal to 0.04 µg/l compared with those with cTnI of less than 0.04 µg/l [758 (493-1536 ) pg/ml vs. 454 (167-899) pg/ml; P=0.0037]. A significant correlation (r=0.323, P=0.0045) was found between sRAGE and cTnI levels in patients with NSTE-ACS. Plasma sRAGE levels are elevated in patients with NSTE-ACS with positive cTnI, suggesting that they could be related to myocardial cell damage.

Soluble Receptor for Advanced Glycation End Products (sRAGE) is decreased in patients with Juvenile Idiopathic Arthritis (ERA category) and inversely correlates with disease activity and S100A12 levels

Objective. Membrane-bound receptor for advanced glycation endproducts (mRAGE) is overexpressed in response to increasing concentrations of its ligand (e.g., S100A12) and triggers an inflammatory immune response. In contrast, soluble RAGE (sRAGE) acts as a decoy receptor and downmodulates inflammation. Decreased sRAGE levels are associated with autoimmune diseases; however, limited data are available in juvenile idiopathic arthritis (JIA). We studied sRAGE levels in patients with JIA [enthesitis-related arthritis (ERA) category]. Methods. sRAGE levels were estimated in the serum of patients with ERA JIA (n = 101), systemic-onset JIA and polyarticular JIA (n = 10 each), and healthy controls (n = 45). Synovial fluid (SF) sRAGE was measured in patients with ERA, rheumatoid arthritis, reactive arthritis, and osteoarthritis (n = 10). Levels of S100A12 were also measured. Twenty-four patients with ERA were followed for 4 months. Disease activity was assessed by swollen joint count (SJC), tender joint count (TJC), and erythrocyte sedimentation rate (ESR). All levels are expressed as median (range). Results. The serum sRAGE (pg/ml) level was significantly lower in patients compared to healthy controls [515 (64–1887) vs 1542 (627–3159); p < 0.0001]. In paired samples, SF had lower levels compared to corresponding plasma level [102 (51–799) vs 481 (134–1006); p < 0.0001]. The level of S100A12 (ng/ml) was higher in SF (1042; 573–1415) than serum (638; 208–779). Serum sRAGE correlated negatively with S100A12 levels (r = −0.474; p < 0.01.), ESR (r = −0.306; p < 0.01), and SJC (r = −0.237; p < 0.05), but not with TJC (r = −0.134; p = NS). The levels of sRAGE remained stable over time in patients with stable disease. Conclusion. Levels of sRAGE are reduced in patients with ERA and correlate negatively with disease activity and S100A12 levels. sRAGE may be a modulator of inflammation in these patients.

Soluble Receptor for Advanced Glycation Endproducts Is Decreased in Patients with Juvenile Idiopathic Arthritis (ERA Category) and Inversely Correlates with Disease Activity and S100A12 Levels

Membrane-bound receptor for advanced glycation endproducts (mRAGE) is overexpressed in response to increasing concentrations of its ligand (e.g., S100A12) and triggers an inflammatory immune response. In contrast, soluble RAGE (sRAGE) acts as a decoy receptor and downmodulates inflammation. Decreased sRAGE levels are associated with autoimmune diseases; however, limited data are available in juvenile idiopathic arthritis (JIA). We studied sRAGE levels in patients with JIA [enthesitis-related arthritis (ERA) category]. sRAGE levels were estimated in the serum of patients with ERA JIA (n = 101), systemic-onset JIA and polyarticular JIA (n = 10 each), and healthy controls (n = 45). Synovial fluid (SF) sRAGE was measured in patients with ERA, rheumatoid arthritis, reactive arthritis, and osteoarthritis (n = 10). Levels of S100A12 were also measured. Twenty-four patients with ERA were followed for 4 months. Disease activity was assessed by swollen joint count (SJC), tender joint count (TJC), and erythrocyte sedimentation rate (ESR). All levels are expressed as median (range). The serum sRAGE (pg/ml) level was significantly lower in patients compared to healthy controls [515 (64-1887) vs 1542 (627-3159); p < 0.0001]. In paired samples, SF had lower levels compared to corresponding plasma level [102 (51-799) vs 481 (134-1006); p < 0.0001]. The level of S100A12 (ng/ml) was higher in SF (1042; 573-1415) than serum (638; 208-779). Serum sRAGE correlated negatively with S100A12 levels (r = -0.474; p < 0.01.), ESR (r = -0.306; p < 0.01), and SJC (r = -0.237; p < 0.05), but not with TJC (r = -0.134; p = NS). The levels of sRAGE remained stable over time in patients with stable disease. Levels of sRAGE are reduced in patients with ERA and correlate negatively with disease activity and S100A12 levels. sRAGE may be a modulator of inflammation in these patients.

Relation of Soluble Receptor for Advanced Glycation End Products to Predict Mortality in Patients With Chronic Heart Failure Independently of Seattle Heart Failure Score

Knowledge of the role of the soluble receptor for advanced glycation end products (sRAGEs) in chronic heart failure (CHF) is very limited. In the present study, we measured plasma sRAGE levels in patients with CHF and examined whether plasma sRAGE predicts prognosis in patients with HF independently of validated scores as the Seattle Heart Failure Score (SHFS). We measured plasma sRAGE in 106 outpatients with CHF. Patients were prospectively followed during a median follow-up period of 1.3 years with end points of cardiac death or rehospitalization. Plasma sRAGE level increased with advancing New York Heart Association functional class, SHFS, age, and ischemic cause. Plasma sRAGE level was also higher in patients with cardiac death and/or events than in event-free patients. In Cox multivariate proportional hazard analysis, SHFS, sRAGE, and N-terminal pro-B-type natriuretic peptide were independent risk factors for cardiac death (sRAGE hazard ratio 1.26, 95% confidence interval 1.09 to 1.45, p = 0.002) and/or cardiac events (sRAGE hazard ratio 1.07, 95% confidence interval 1.03 to 1.11, p = 0.002). Survival curves adjusted by Cox analysis clearly demonstrated that the high-sRAGE group (higher than median) had a significantly higher incidence of cardiac death than the low-sRAGE group (p = 0.001). In conclusion, sRAGE is a novel, highly sensitive, and specific prognostic marker in current optimally treated patients with CHF with an additive and independent value compared to the multimarker SHFS.

A novel mechanism of action of atorvastatin against cardiovascular risk: A commentary on “Decreased plasma soluble RAGE in patients with hypercholesterolemia: effects of statins”

Growing evidence derived from clinical studies has recentlyfostered the idea that the soluble form of the receptor foradvanced glycation endproducts (sRAGE) might serve as avaluable risk marker for several RAGE-mediated disorders.Accordingly, circulating levels of sRAGE have been found tobe reduced in a number of diverse clinical conditions, includingcoronary atherosclerosis [1], hypertension [2], type 2 diabetes[3],Alzheimerdisease[4],andrheumatoidarthritis[5].BecauseRAGE has been shown to act as a decoy binding inflammatoryRAGE ligands like advanced glycation endproducts (AGEs)[6], it has been speculated that RAGE might counteractinflammatory reflexes triggered by RAGE ligands such asAGEs, S100 proteins, and HMGB1 [7].The potential therapeutic usefulness of genetically engi-neeredsRAGEforpreventionandtreatmentofRAGE-mediateddisorders has been demonstrated in numerous animal studies[8]. Thus far, however, the limited data on the pathophysiolo-gical mechanisms regulating sRAGE production in humanshave hampered the therapeutic application of soluble RAGE inhuman disease states. To gain more insight into this crucialchallenge, first it would be necessary to shed more light on howcurrent pharmacological agents could modulate circulatinglevels of sRAGE in human beings. In this regard, Forbes et al.[9] have previously shown that inhibition of angiotensin-converting enzyme increased plasma sRAGE levels in bothdiabetic rats and humans with type 1 diabetes.A new intriguing paper by Santilli and colleagues [10] takesthe next step in showing how sRAGE levels might actually bemodulated by cardiovascular drugs. In a sample of Italiannondiabetic subjects with hypercholesterolemia, these authorsshowlowerendogenouslevelsofsRAGEthatweresignificantlyreversed after 8 weeks of statin treatment with atorvastatin(20 mg/day) but not with pravastatin (40 mg/day). Notably, thiseffect seemed to occur independent of LDL-cholesterolimprovement, which was virtually equal in both treatmentgroups. It is now well recognized that the beneficial effects ofstatins are not entirely related to their lipid-lowering effects, butrather to a number of diverse actions [11]. In this regard, thework of Santilli and colleagues provides a new mechanism ofaction for statins with the observation that atorvastatin mightelevate levels of sRAGE in hypercholesterolemic subjects,regardless of its lipid-lowering effect. Of great interest, we havepreviously shown that a reduced level of sRAGE may act as animportant risk factor for cardiovascular disease even in normo-cholesterolemic subjects [1]. The question as to whetheratorvastatin administration to patients with normocholesterole-mia may reduce cardiovascular risk through an elevation ofplasma sRAGE levels remains open, but future clinical studiesare certainly warranted to address this issue.In addition to confirming preclinical studies showing thatstatins might modulate the AGE–RAGE system in culture[12,13], the work of Santilli et al. might carry another importantimplication for studies focusing on circulating sRAGE levels inpatients with cardiovascular diseases. By showing that statinscanelevatelevelsofsRAGE,theauthors’findingsimplicatethatthe use of these drugs may act as an important confounder inclinical reports investigating circulating sRAGE concentrationsincohortsofpatientswithcardiovascularormetabolicdisorders.It follows that results of cross-sectional and prospectiveinvestigations on sRAGE as a biomarker should be statisticallyadjusted for statin use to yield reliable information.Whataboutthemolecular mechanismsof actionofstatins onsRAGE levels? A previous report has suggested that statinsmight inhibit RAGE activation by reducing myeloperoxidase-

Receptor for advanced glycation end-products (RAGE) - soluble form (sRAGE) and gene polymorphisms in patients with breast cancer

21113 Background: Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome.. Our aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. Methods: We studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and C-erb B2 receptors) and in 92 healthy controls. Results: Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 ± 777 vs. 1803 ± 632 ng/ml, p &lt; 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors and intermediate positivity of C-erb B2 (Her-neu) receptors and were also influenced genetically (G82S and 2184 AG polymorphisms of the RAGE gene). Conclusions: Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (with low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression. No significant financial relationships to disclose.