Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients

BACKGROUND:

Interaction of the receptors for advanced glycation end products (RAGEs) with advanced glycation end products (AGEs) results in expression of inflammatory mediators (tumor necrosis factor-alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]), activation of nuclear factor-kappa B and induction of oxidative stress – all of which have been implicated in atherosclerosis. Soluble RAGE (sRAGE) acts as a decoy for the RAGE ligand and is protective against atherosclerosis.

OBJECTIVES:

To determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs, TNF-α and sVCAM-1 are higher in non-ST elevation myocardial infarction (NSTEMI) patients than in healthy control subjects; and whether sRAGE or the ratio of AGEs to sRAGE (AGEs/sRAGE) is a predictor/biomarker of NSTEMI.

METHODS:

Serum levels of sRAGE, AGEs, TNF-α and sVCAM-1 were measured in 46 men with NSTEMI and 28 age- and sex-matched control subjects. Angiography was performed in the NSTEMI patients.

RESULTS:

sRAGE levels were lower, and levels of AGEs, TNF-α, sVCAM-1 and AGEs/sRAGE were higher in NSTEMI patients than in control subjects. sRAGE levels were negatively correlated with the number of diseased coronary vessels, serum AGEs, AGEs/sRAGE, TNF-α and sVCAM-1. The sensitivity of the AGEs/sRAGE test is greater than that of the sRAGE test, while the specificity and predictive values of the sRAGE test are greater than those of the AGEs/sRAGE test for identifying NSTEMI patients.

CONCLUSIONS:

Serum levels of sRAGE were low in NSTEMI patients, and were negatively correlated with extent of lesion, inflammatory mediators, AGEs and AGEs/sRAGE. Both sRAGE and AGEs/sRAGE may serve as biomarkers/predictors for identifying NSTEMI patients.     

Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects

The advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis is implicated in diabetic vascular complications. Administration of soluble form of RAGE (sRAGE) to mice has been shown to block the AGE-elicited tissue damage by acting as a decoy. These observations suggest that endogenous sRAGE may capture and eliminate circulating AGEs and decrease its serum levels. However, because AGEs up-regulate tissue RAGE expression and endogenous sRAGE could be generated from the cleavage of cell surface RAGE, sRAGE may be positively, rather than inversely, associated with circulating AGEs by reflecting tissue RAGE expression. In this study, we investigated the association of sRAGE with serum levels of AGEs in humans. Data for fasting serum sRAGE and AGE levels of 184 nondiabetic subjects were obtained from a general population in Japan. We also measured body mass index (BMI), waist circumference, blood pressure, and blood biochemistries in this population. Uni- and multivariate analyses were applied for the determinants of serum sRAGE levels. The average sRAGE levels were 0.40 +/- 0.17 ng/mL in males and 0.43 +/- 0.14 ng/mL in females, respectively. In the univariate analysis, BMI (P < .05, inversely), waist circumference (P < .05, inversely), AGEs (P < .05), and alcohol intake (P < .05, inversely) were significantly associated with sRAGE levels. After performing multivariate analyses, BMI (P < .05, inversely) and AGEs (P < .05) still remained significant independently. The present study is the first demonstration that serum sRAGE levels were positively associated with circulating AGEs in the nondiabetic general population. Endogenous sRAGE levels are elevated in parallel with serum AGE levels.     

Low plasma levels of the soluble receptor for advanced glycation end products in HIV-infected patients with subclinical carotid atherosclerosis receiving combined antiretroviral therapy

Objective

Combined antiretroviral therapy (cART) has significantly improved the survival rate and quality of life for HIV-infected subjects, but it contributes to the development of metabolic complications including coronary artery disease (CAD). Recent studies have reported that high plasma levels of the soluble receptor for advanced glycation end products (sRAGE) were associated with a lower incidence of CAD in non-HIV infected patients. However, there has been no report of an association of sRAGE and subclinical carotid atherosclerosis in HIV-infected patients receiving cART.

Methods

We examined the association of circulating sRAGE in HIV-infected patients with carotid intima–media thickness (IMT) and other metabolic variables. We prospectively enrolled 76 HIV-infected patients receiving cART for ≥6 months.

Results

sRAGE had a significantly negative correlation with body mass index (r = −0.324, p = 0.005), waist-to-hip ratio (r = −0.335, p = 0.003), systolic blood pressure (BP) (r = −0.359, p = 0.002), diastolic BP (r = −0.343, p = 0.004), total cholesterol (r = −0.240, p = 0.037), low-density lipoprotein-cholesterol (r = −0.284, p = 0.024), log(homeostasis model assessment of insulin resistance [HOMA-IR]) (r = −0.380, p = 0.002) and carotid IMT including max-IMT and mean-IMT (r = −0.358, p = 0.001 and r = −0.329, p = 0.004, respectively). By the use of multiple stepwise regression analyses, systolic BP (p = 0.001) and log[HOMA-IR] (p = 0.001) remained significant independently.

Conclusions

These results suggest that sRAGE may have a protective effect against subclinical atherosclerosis by preventing inflammatory responses mediated by the activation of cell surface RAGE in HIV-infected patients receiving cART.     

Independent determinants of soluble form of receptor for advanced glycation end products in elderly hypertensive patients

Advanced glycation end product receptor (RAGE) interaction plays an important role in atherosclerosis. Although exogenously administered soluble form of RAGE (sRAGE) has been shown to suppress the development and progression of atherosclerosis in animals, the kinetics and role of endogenous sRAGE in humans are not fully understood. In this study, to clarify whether endogenous sRAGE could capture and efficiently eliminate RAGE ligands such as circulating AGEs and high-mobility group box-1 (HMGB-1), we investigated the correlation between sRAGE and RAGE ligands and examined independent determinants of serum levels of sRAGE in hypertensive humans. Two-hundred seventy-one consecutive nondiabetic outpatients with essential hypertension (83 male and 188 female; mean age, 76.5 ± 9.2 yeas) underwent a complete history, physical examination, and determination of blood chemistries, including serum levels of sRAGE, AGEs, and HMGB-1. Univariate regression analysis showed that serum levels of sRAGE were associated with body mass index (r = −0.313, P < .0001), waist (r = −0.214, P < .0001), alanine aminotransferase (r = −0.172, P = .005), γ-glutamyltranspeptidase (r = −0.213, P < .0001), 24-hour creatinine clearance (r = −0.348, P < .0001), B-type natriuretic peptide (r = 0.138, P = .027), tumor necrosis factor-α (r = 0.138, P = .002), and alcohol intake (r = −0.155, P = .010). By the use of multiple stepwise regression analyses, 24-hour creatinine clearance (P < .0001), γ-glutamyltranspeptidase (P < .001), body mass index (P = .007), and tumor necrosis factor-α (P = .024) remained significant independently. The present study demonstrated for the first time that there was no significant correlation between serum levels of sRAGE and RAGE ligands such as circulating AGEs and HMGB-1 in hypertensive patients. Anthropometric and inflammatory variables and liver and renal function may be the determinants of endogenous sRAGE levels in nondiabetic hypertensive patients.     

The different roles for the advanced glycation end products axis in heart failure and acute coronary syndrome settings

AimsThis work aimed to compare the behavior of the advanced glycation end products (AGEs) and their soluble receptor (sRAGE) in two cohorts of patients: those with heart failure (HF) and acute coronary syndrome (ACS).Methods and resultsA unicentric observational clinical study was performed in 102 patients with ACS and 102 patients with chronic HF matched by age and gender. At inclusion, fluorescent AGEs were measured by quantitative fluorescence spectroscopy of plasma, and total sRAGE and endogenous secretory RAGE (esRAGE) levels were determined by enzyme-linked immunosorbent assay kits. A 5-year follow-up period was established for recording cardiac death (primary endpoint) and the incidence of non-fatal myocardial infarction or HF readmission (secondary endpoints). Higher glycation parameters were observed in HF patients, whereas no differences in sRAGE forms were found between HF and ACS cohorts, except for cRAGE, which was higher in HF. Associations between glycation parameters and sRAGE forms were observed in HF, but not in ACS. Differences were also evidenced in the long-term prognosis of each cohort: esRAGE showed an independent prognostic value for cardiac death or non-fatal cardiovascular events in HF, but none of the AGE–RAGE variables were predictors in ACS.ConclusionsA different role for the AGE–RAGE axis was observed in HF and ACS. All the sRAGE forms were directly related with glycation parameters in HF, but not in ACS. The independent value of the sRAGE forms on each cardiovascular disease was supported by esRAGE being an independent predictor of bad long-term prognosis only for HF.     

Role of advanced glycation end product (AGE)-induced receptor (RAGE) expression in diabetic vascular complications

AimsVascular complications are the major causes of morbidity and mortality in diabetic subjects. Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) induces signal transduction that culminates in vascular complications. Therefore, in the present study we investigated the dependence of RAGE expression on circulating AGEs and evaluated the outcome of AGE–RAGE interaction by the oxidative stress and nature of vascular complications in type 2 diabetes mellitus (T2DM) patients.MethodsRAGE expression was determined by quantitative real-time PCR and western blotting, serum AGEs were estimated by ELISA and spectrofluorometry and oxidative stress markers namely protein carbonyl (PCO), advanced oxidation protein products (AOPP) and lipid peroxidation (MDA) were assayed spectrophotometerically in 75 T2DM patients (DM without vascular complication n = 25; DM with microvascular complications n = 25; DM with macrovascular complications n = 25) and 25 healthy controls.ResultsSerum AGE level was significantly higher in diabetic patients having vascular complications as compared to T2DM without complications (p < 0.01). RAGE m-RNA expression level in PBMCs assayed by quantitative real time PCR was four times higher in diabetic subjects without vascular complications while DM patients having microvascular and macrovascular complications showed 12 fold and 8 fold higher RAGE m-RNA expression respectively compared to healthy controls. Circulating AGE level showed significant positive correlation with RAGE m-RNA expression and oxidative stress markers.ConclusionAGE-mediated exacerbation of RAGE expression may contribute to oxidative stress generation that plays a key role in pathogenesis of vascular complications in diabetes.     

Advanced glycation end products in diabetic and non-diabetic human subjects suffering from cataract

Advanced glycation end products (AGEs) play a pivotal role in loss of lens transparency, i.e., cataract. AGEs formation occurs as a result of sequential glycation and oxidation reaction between reducing sugars and protein. AGEs production takes place throughout the normal aging process but its accumulation is found to be more rapid in diabetic patients. In this study, we quantified AGEs and N-(carboxyethyl) lysine (CEL) in human cataractous lenses from non-diabetic (n = 50) and diabetic patients (n = 50) using ELISA. We observed significantly higher (p < 0.001) levels of lens AGEs and CEL in diabetic patients with cataract as compared with their respective controls. The presence of AGEs and CEL was also determined by western blotting and immuno-histochemical analysis. Furthermore, isolated β-crystallin from cataractous lenses of non-diabetic and diabetic patients was incubated with different sugars to evaluate the extent of glycation in a time dependent manner. Our data indicated more pronounced glycation in patients suffering from diabetes as compared to non-diabetics subjects demonstrating the need to focus on developing normoglycemic approaches. Such studies may provide an insight in developing therapeutic strategies and may have clinical implications.     

Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes

Aims/hypothesis Interfering with the activation of receptor for AGE (RAGE) by using a soluble form of the AGE receptor (sRAGE) prevents or ameliorates the vascular complications of diabetes in experimental studies. Relatively little is known about factors that influence endogenous circulating sRAGE in humans. We investigated the impact of improving glycaemic control on serum total sRAGE and endogenous secretory RAGE (esRAGE), a splice variant of sRAGE, and compared the effect of rosiglitazone with that of sulfonylurea. Methods A randomised, open-label, parallel group study was performed with 64 participants randomised to receive add-on therapy with either rosiglitazone or sulfonylurea. Serum total sRAGE and esRAGE and metabolic parameters were measured before and after 6 months of treatment. Results At 6 months, both rosiglitazone and sulfonylurea resulted in a significant reduction in HbA_1c, fasting glucose and AGE. However, significant increases in total sRAGE and esRAGE were only seen in the rosiglitazone group. As a result, serum esRAGE was higher in the rosiglitazone group than in the sulfonylurea group at 6 months (p < 0.01), whereas the differences in sRAGE between the two groups did not reach statistical significance. Stepwise linear regression analysis showed that treatment modality made a greater contribution than the changes in HbA_1c to the subsequent changes in esRAGE levels at 6 months. Conclusions/interpretation Treating type 2 diabetic patients with thiazolidinedione can increase circulating levels of esRAGE and sRAGE. Whether modulation of circulating sRAGE has a beneficial effect on diabetic complications will have to be evaluated in long-term prospective studies. International Standard Randomised Controlled Trial Number ISRCTN05215453.     

Serum soluble receptor for advanced glycation end‐products during acute bronchiolitis in infant: Prospective study in 93 cases

Introduction

Acute bronchiolitis is a major cause of acute respiratory distress in infants. The soluble receptor for advanced glycation end‐products (sRAGE) is a biomarker of pulmonary damage processes, with a diagnostic and a prognostic value in acute respiratory distress syndrome (ARDS). The RAGE pathway is also implicated in the pathogenesis of other respiratory diseases like asthma, but the value of sRAGE levels in acute bronchiolitis remains under‐investigated.

Material and methods

A prospective, observational, and analytical study was conducted at Clermont‐Ferrand University Hospital. The main objective was to evaluate the correlation between serum sRAGE and clinical severity of bronchiolitis in hospitalized infants aged <1 year. We analyzed correlations between serum sRAGE and Wainwright score, short‐term morbidity attributable to bronchiolitis, causal viruses and risk for recurrent wheezing at 1 year.

Results

The study included 93 infants. sRAGE levels were significantly lower in acute bronchiolitis patients (mean 1101 pg/mL) than in controls (2203 pg/mL, P < 0.001) but did not correlate with clinical severity. No correlation was found between serum sRAGE and severity score, respiratory viruses, and recurrent wheezing at 1 year. Serum sRAGE levels were negatively correlated with age (r = −0.45, P < 0.001).

Conclusion

Serum sRAGE levels are decreased in acute bronchiolitis but not correlated with disease severity. sRAGE levels should be age‐adjusted in infants. Serum sRAGE levels measured in the setting of acute bronchiolitis were not predictive of recurrent wheezing.

     

Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease

BACKGROUND: Advanced glycation end products (AGEs)-receptor (RAGE) axis is implicated in diabetic vascular complication. Since a soluble form of RAGE (sRAGE) could be generated from the cleavage of cell surface RAGE in endothelial cells (ECs), serum sRAGE levels may be elevated in diabetes consequent to EC damage. In this study, we examined whether sRAGE levels were elevated in type 2 diabetic patients compared with non-diabetic healthy subjects. METHODS: Serum sRAGE levels were examined in 75 Japanese type 2 diabetic patients (29 men and 46 women; mean age 66 +/- 11 years) and 75 age- and sex-matched non-diabetic healthy control subjects. We explored the association between sRAGE levels and coronary artery disease (CAD) in diabetic patients. RESULTS: Serum sRAGE levels were significantly higher in diabetic patients than in non-diabetic subjects (965.3 +/- 544.2 vs 415 +/- 150.4 pg/mL, p < 0.001). In the univariate analysis, diastolic blood pressure (inversely), LDL cholesterol, triglycerides, HDL cholesterol, hemoglobin A(1c), and creatinine were significantly associated with sRAGE. After performing multivariate analyses, the presence of diabetes (p < 0.0001) was a sole independent determinant of sRAGE. Furthermore, there was a significant difference in sRAGE levels between diabetic patients with CAD and those without CAD (1680.6 +/- 891.1 vs 855.2 +/- 372.1 pg/mL, p < 0.001). Multiple stepwise regression analysis revealed that sRAGE and creatinine levels were independent determinants of CAD. CONCLUSIONS: The present study demonstrated that serum sRAGE levels were significantly higher in type 2 diabetic patients than in non-diabetic subjects and positively associated with the presence of CAD.     

Correlation between soluble receptor for advanced glycation end products levels and coronary artery disease in postmenopausal nondiabetic women

BACKGROUNDThe established cardiovascular risk factors cannot explain the overall risk of coronary artery disease (CAD), especially in women. Therefore, there is a growing need for the assessment of novel biomarkers to identify women at risk. The receptor for advanced glycation end products (RAGE) and its interaction with the advanced glycation end product (AGE) ligand have been associated with atherogenesis. The soluble fraction of RAGE (sRAGE) antagonizes RAGE signaling and exerts an antiatherogenic effect.AIMThe study aim was to explore the association between plasma levels of sRAGE and CAD in nondiabetic postmenopausal women.METHODSThis case-control study included 110 nondiabetic postmenopausal women who were enrolled in two groups. Group I included 55 angiographically proven CAD subjects with > 50% stenosis in at least one of the major coronary arteries and Group II included 55 healthy control women who did not have CAD or had < 50% stenosis of the coronary arteries. Stenosis was confirmed by invasive angiography. Plasma sRAGE was determined by an enzyme-linked immunosorbent assay.RESULTSWe observed significantly lower plasma sRAGE concentrations in subjects with CAD vs healthy controls (P < 0.05). Univariate and multivariate logistic regression analysis also revealed a significant correlation between plasma sRAGE levels and CAD (P = 0.01). Multivariate odds ratios for CAD revealed that subjects with sRAGE concentrations below 225 pg/mL (lowest quartile) had a 6-fold increase in CAD prevalence independent of other risk factors.CONCLUSIONOur findings indicated that low sRAGE levels were independently associated with CAD in nondiabetic postmenopausal women. Risk assessment of CAD in postmenopausal women can be improved by including sRAGE along with other risk factors.     

Serum levels of low molecular weight advanced glycation end products in diabetic subjects

AIMS: One of the principal theories of the development of diabetic complications proposes that increased levels of advanced glycation end products (AGE) are formed in diabetes by prolonged exposure of proteins, lipids and nucleotides to glucose. Such AGEs may contribute to the development of diabetic complications by a number of mechanisms. Circulating AGEs can be detected in serum, and in the present study, we analysed the clinical correlates of circulating serum low molecular weight AGE (LMW-AGE). METHODS: Serum LMW-AGE was measured in 106 non-diabetic and 499 diabetic subjects using fluorescence spectroscopy. Results were calibrated against an in-house AGE albumin preparation, and expressed as absolute fluorescence units (AFU). RESULTS: Serum LMW-AGE values were significantly higher in diabetic than non-diabetic subjects [median 7.5 (range 0-595.5) vs. 5.3 (1.0-15.5) AFU, P<0.01]. In the normal subjects, there were significant correlations between serum LMW-AGE and age (r=0.42, P<0.01) and serum creatinine (r=0.39, P<0.01). In the diabetic patients, serum LMW-AGE correlated significantly with age (r=0.315, P<0.01), systolic blood pressure (r=0.141, P=0.002), serum creatinine (r=0.449, P<0.01) and urinary albumin/creatinine ratio (ACR) (r=0.265, P<0.01). There was no correlation between serum LMW-AGE and HbA1c. On regression analysis, with serum LMW-AGE as the dependent variable, serum creatinine emerged as the most significant factor (t=8.1, P<0.01), followed by age (t=4.0, P<0.01) and ACR (t=2.9, P=0.004). There was no significant difference in serum LMW-AGE between those with and without retinopathy or in those with vascular disease. CONCLUSIONS: We conclude that circulating LMW-AGEs are increased in diabetic subjects. The major determinant appears to be renal dysfunction in the form of raised albumin/creatinine ratio or creatinine. There was no association with other markers of vascular disease or presence of diabetic complications.     

Advanced glycation end-products in senile diabetic and non-diabetic patients with cardiovascular complications

Advanced glycation end products (AGEs) have been reported to contribute to aging and cardiovascular complications. In the present study, the immunoreactivity of AGEs in human serum samples of healthy older subjects (n = 31), senile diabetic patients without cardiovascular complications (n = 33), senile diabetic patients with cardiovascular complications (n = 32), senile non-diabetic patients with cardiovascular complications (n = 30) ,and healthy young subjects (n = 31) were investigated. The patients were selected on clinical grounds from the National Institute of Cardiovascular Disease, Karachi and the Jinnah Postgraduate Medical Centre, Karachi, Pakistan. Fasting blood glucose, HbA_1C and serum fructosamine levels were significantly (P < 0.001) increased in senile diabetic patients with and without cardiovascular complications as compared to non-diabetic senile patients with cardiovascular complications and healthy older subjects. Additionally, serum AGEs were found to be significantly (P < 0.001) increased in senile diabetic patients with cardiovascular complications and senile non-diabetic patients with cardiovascular complications, followed by diabetic patients without cardiovascular complications as compared to healthy older subjects and young control subjects. However, no significant difference was found in the senile diabetic patients without cardiovascular complications and senile non-diabetic patients with cardiovascular complications. In contrast to all four senile groups, serum AGEs were significantly (P < 0.001) lower in young control subjects. The AGEs distribution in the senile groups corroborates the hypothesis that the advanced glycation process might play a role in the development of cardiovascular complications, which are more severe in diabetic patients compared with non-diabetic patients with cardiovascular complications.     

Differential accumulation of advanced glycation end products in the course of diabetic retinopathy

Aims/hypothesis. Glycated proteins, formed by reaction of glucose and protein, react further yielding numerous, mostly undefined advanced glycation end products (AGE). The recently characterized imidazolone-type AGE (AG-1) is non-oxidatively formed involving 3-deoxyglucosone whereas some AGEs, particularly Nɛ-(carboxymethyl)lysine (CML), are formed only in the presence of oxygen. Methods. To study the possible contribution of oxidative and non-oxidative AGE formation in the development of diabetic retinopathy antibodies directed against CML-type and imidazolone-type AGEs were characterized by dot blot analysis and used to localize these well-characterized epitops in the retinas from diabetic rats (early course) and from human Type I (insulin-dependent) diabetes mellitus with laser-treated proliferative diabetic retinopathy (late course). Results. In non-diabetic rats CML was moderately positive in neuroglial and vascular structures of non-diabetic rat retinas and increased strongly in diabetic retinas. Anti-imidiazolone antibody staining was strongly positive only in diabetic capillaries. Advanced human diabetic retinopathy showed strong CML-immunolabelling of the entire retina whereas control samples showed moderate staining of neuroglial structures only with the polyclonal CML-antibody. Anti-imidiazolone antibody staining was faint in the inner retina of control sections but were strong throughout the entire diabetic retina. Immunolabelling for the AGE-receptor was congruent with a marker of Müller cells. Conclusion/interpretation. Our data indicate that the oxidatively formed CML is present in non-diabetic retinas as a regular constituent but increases in diabetes both in neuroglial and vascular components. Imidazolone-type AGE are restricted to microvessels and spread during later stages over the entire retina, co-localizing with the expression of AGE-receptor. [Diabetologia (1999) 42: 728–736] Received: 22 October 1998 and in revised form: 11 January 1999     

慢阻肺急性加重期患者血浆晚期糖基化终末产物和sRAGE研究

目的研究分析慢性阻塞性肺疾病(慢阻肺)患者血浆中晚期糖基化终末产物(AGEs)和可溶性糖基化终末产物受体(sRAGE)的水平及与慢阻肺患者肺功能的关系。方法选取河北省承德县医院收治的120例慢阻肺患者(慢阻肺组)、50例健康人群(对照组),分别检测两组的血浆AGEs、sRAGE及肺功能等指标。结果慢阻肺组患者的血浆中AGEs(36.25±2.98)ug/m L显著的高于对照组的(28.94±2.31)ug/m L,sRAGE为(338.41±194.26)pg/m L显著的低于对照组的(871.50±226.49)pg/m L且差异均具有统计学意义(P0.05)。慢阻肺组患者血浆AGEs与患者的FEV1%呈显著的负相关关系(r=-0.594,P=0.0000.001);慢阻肺组患者血浆sRAGE与患者的FEV1%呈显著的正相关关系(r=0.552,P=0.0000.001)。结论慢阻肺患者血浆中AGEs、sRAGE水平发生显著的改变,AGEs与患者的肺功能呈负相关性、sRAGE与患者的肺功能呈正相关关系。     

Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes

We have recently found that soluble form of receptor for advanced glycation end products (sRAGE) levels are positively associated with inflammatory biomarkers and the presence of coronary artery disease (CAD) in type 2 diabetic patients. Since advanced glycation end products (AGEs) up-regulate RAGE expression and endogenous sRAGE could be generated from the cleavage of cell surface RAGE, it is conceivable that sRAGE is positively associated with circulating AGEs levels in diabetes. In this study, we examined whether sRAGE were correlated to circulating levels of AGEs and soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in patients with type 2 diabetes. Eighty-two Japanese type 2 diabetic patients underwent a complete history and physical examination, determination of blood chemistries, sRAGE, AGEs, sVCAM-1 and sICAM-1. Multiple regression analysis revealed that serum levels of AGEs and sVCAM-1 were independently correlated with sRAGE. This study demonstrated that serum levels of sRAGE were positively associated with circulating AGEs and sVCAM-1 levels in type 2 diabetic patients. Our present observations suggest sRAGE level may be elevated in response to circulating AGEs, thus being a novel marker of vascular injury in patients with type 2 diabetes.     

Relationship between advanced glycation end products and increased lipid peroxidation in semen of diabetic men

Aims

Majority of diabetic male patients have disturbances in their reproductive systems. However, the mechanisms underlying these disturbances are largely unknown. Since advanced glycation end products (AGE) have a key role in oxidative stress and cell damage in diabetic complications, we hypothesize that AGEs may be involved sperm lipid peroxidation.

Methods

Total AGEs in seminal plasma of 32 diabetic and 35 non-diabetic men was determined by spectrofluorimetric method and carboxy methyl lysine (CML) level was assayed using ELISA. Contents of lipid peroxidation in sperm and seminal plasma were determined by thiobarbituric acid reaction. Total antioxidant capacity (TAC) was measured by a colorimetric assay.

Results

Total AGEs were found significantly higher in seminal plasma of diabetic men than non-diabetic group (p < 0.001) whereas no significant differences in seminal plasma CML values between two groups was observed. Moreover, sperm and seminal plasma lipid peroxidation were significantly higher in diabetic subjects than non-diabetic men and a significantly lower TAC was detected in diabetic group compare to non-diabetics.

Conclusions

These results showed an increment in AGEs in seminal plasma of diabetic subjects and may suggest a key role for glycation process and increased oxidative stress in reproductive system dysfunction.     

Soluble receptors for advanced glycation end products (sRAGE) as a predictor of restenosis following percutaneous coronary intervention

Background:

Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) increases expression of inflammatory mediators (tumor necrosis factor alpha [TNF‐α] and soluble vascular cell adhesion molecule‐1 [sVCAM‐1]) and induces oxygen radicals that are implicated in atherosclerosis. Balloon‐injury‐induced atherosclerosis is associated with increased expression of AGEs and RAGE. The soluble receptor for AGE (sRAGE), which acts as a decoy for RAGE ligands (AGEs), prevents atherosclerosis in this model.

Hypothesis:

We evaluated: 1) whether post‐percutaneous coronary intervention (PCI) restenosis is associated with low pre‐PCI serum sRAGE, high serum AGEs, TNF‐α, and sVCAM‐1, and high AGE/sRAGE ratio; 2) whether pre‐PCI and post‐PCI levels of these markers are similar in patients with or without restenosis; and 3) whether sRAGE and AGE/sRAGE ratio have predictive value for post‐PCI restenosis.

Methods:

Angiography was performed in 46 patients with non–ST‐segment elevation myocardial infarction for assessment of restenosis. Serum sRAGE, AGEs, TNF‐α, and sVCAM‐1 were measured in these patients and 20 control subjects.

Results:

Nineteen of the 46 patients developed post‐PCI restenosis, which was associated with lower sRAGE and higher TNF‐α and sVCAM‐1 levels, and higher AGE/sRAGE ratio compared with patients without restenosis. Pre‐PCI and post‐PCI levels of these biomarkers were similar in both groups, except in patients with restenosis, in whom the post‐PCI level of sRAGE was lower and TNF‐α was higher than the pre‐PCI levels. The sensitivity and negative predictive value of sRAGE were 100%, and were higher than those of AGE/sRAGE ratio in identifying post‐PCI restenosis.

Conclusions:

Both low serum sRAGE levels and high AGE/sRAGE ratio have predictive value for post‐PCI restenosis. Copyright © 2008 Wiley Periodicals, Inc. This research was supported by grants from the Heart and Stroke Foundation of Saskatchewan and the Pollack Research Foundation, Saskatoon, Saskatchewan. The authors have no other funding, financial relationships, or conflicts of interest to disclose.     

Correlation between serum advanced glycation end products and dietary intake of advanced glycation end products estimated from home cooking and food frequency questionnaires

Background & aimsTo our knowledge the association between dietary advanced glycation end-products (dAGEs) and cardiometabolic disease is limited. Our aim was to examine the association between dAGEs and serum concentration of carboxymethyl-lysine (CML) or soluble receptor advanced glycation end-products (sRAGEs), and to assess the difference on dAGEs and circulating AGEs according to lifestyle and biochemical measures.Methods and results52 overweight or obese adults diagnosed with type 2 diabetes were included in this cross-sectional analysis. dAGEs were estimated from a Food Frequency Questionnaire (FFQ) or from a FFQ + Home Cooking Frequency Questionnaire (HCFQ). Serum concentrations of CML and sRAGEs were measured by ELISA. Correlation tests were used to analyze the association between dAGEs derived from the FFQ or FFQ + HCFQ and concentrations of CML or sRAGEs. Demographic characteristics, lifestyle factors and biochemical measures were analyzed according to sRAGEs and dAGEs using student t-test and ANCOVA.A significant inverse association was found between serum sRAGEs and dAGEs estimated using the FFQ + HCFQ (r = −0.36, p = 0.010), whereas no association was found for dAGEs derived from the FFQ alone. No association was observed between CML and dAGEs. dAGEs intake estimated from the FFQ + HCFQ was significantly higher among younger and male participants, and in those with higher BMI, higher Hb1Ac levels, longer time with type 2 diabetes, lower adherence to Mediterranean diet, and higher use of culinary techniques that generate more AGEs (all p values p < 0.05).ConclusionsThese results show knowledge on culinary techniques is relevant to derive the association between dAGEs intake and cardiometabolic risk factors.     

Circulating soluble receptor for advanced glycation end products is inversely associated with body mass index and waist/hip ratio in the general population

Advanced glycation end products, AGEs, and its specific receptor, RAGE, are involved in vascular complications. A role for the soluble form of RAGE (sRAGE), which acts as a decoy for AGE, has been documented in patients with diabetes but no information is available in non-diabetic subjects. The aim of this study was to investigate the association of plasma levels of sRAGE with cardiometabolic risk factors in the general population. In addition we evaluated the relation of the common -374A/T polymorphism of RAGE with plasma levels of sRAGE. One hundred and seventy-six healthy subjects free of diabetes or coronary artery disease untreated for hypertension, dyslipidemia or cardiometabolic related diseases were randomly selected for this study from the general population. Plasma sRAGE were negatively and significantly correlated with BMI, waist/hip circumference ratio and fasting glycemia, while a positive correlation was observed with apolipoprotein A-I. These correlations were observed mainly in women who showed significantly higher sRAGE levels (1744+/-660 pg/mL vs 1414+/-649 pg/mL; P<0.05). In a stepwise regression analysis waist circumference was independently associated with sRAGE and, when waist circumference was excluded, BMI was independently associated with sRAGE. Finally in overweight subjects (BMI>25 kg/m(2)) plasma sRAGE was significantly lower compared to lean subjects (1460+/-640 pg/mL vs 1710+/-693 pg/mL; P<0.05). In healthy subjects plasma levels of sRAGE were negatively correlated with BMI and waist/hip ratio supporting a possible protective role for these proteins before any evidence of diabetic or vascular complications.