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.     

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.     

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.     

Circulating advanced glycation end products (AGEs) and soluble form of receptor for AGEs (sRAGE) are independent determinants of serum monocyte chemoattractant protein-1 (MCP-1) levels in patients with type 2 diabetes

BACKGROUND: Atherosclerosis is an inflammatory disease. Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine responsible for the recruitment of monocytes to inflammatory lesions in the vasculature, an initial step of atherosclerosis. Since serum levels of MCP-1 are higher in patients with type 2 diabetes, inhibition of MCP-1 may be a novel therapeutic target for prevention of accelerated atherosclerosis in diabetes. However, little is known about the regulation and determinants of serum MCP-1 levels in patients with diabetes. In this study, we examined the determinants of serum MCP-1 levels in type 2 diabetic patients. METHODS: Eighty-six consecutive outpatients with type 2 diabetes (36 male and 50 female; mean age 68.4+/-9.6) underwent a complete history and physical examination, determination of blood chemistries, MCP-1, tumour necrosis factor-alpha, adiponectin, advanced glycation end products (AGEs), and soluble form of receptor for AGEs (sRAGE). We examined the association between MCP-1 levels and those in anthropometric, metabolic and inflammatory variables in these subjects. RESULTS: Univariate regression analysis showed that serum levels of MCP-1 were positively associated with AGEs (r=0.386, p<0.001) and sRAGE (r=0.315, p<0.001). After adjusting for age and sex, AGEs (p<0.001) and sRAGE (p<0.05) still remained significant. CONCLUSION: The results demonstrate for the first time that circulating levels of AGEs and sRAGE are independent determinants of serum MCP-1 levels in patients with type 2 diabetes. Our present observations suggest the AGEs-RAGE system may be mainly involved in the elevation of MCP-1 in type 2 diabetic patients.     

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.     

The levels of soluble adhesion molecules in diabetic and nondiabetic patients with combined hyperlipoproteinemia and the effect of ciprofibrate therapy

Cell adhesion molecules are thought to play a role in atherosclerosis. Several clinical trials have shown that fibrate treatment leads to a reduction in coronary events, although the mechanisms are not fully understood. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin plasma concentrations were measured in 10 obese dyslipidemic men (group A), in 10 obese dyslipidemic type 2 diabetic men without coronary artery disease (CAD) (group B), and in 10 dyslipidemic type 2 diabetic men with angiographically documented CAD (group C) before and after 12 weeks of treatment with ciprofibrate. Compared with nondiabetic dyslipidemic men, diabetic patients with CAD or without documented CAD had significantly increased levels of sVCAM-1 (512 +/-39 versus 750 +/-139 ng/mL; p<0.0001 and 566 +/-78 ng/mL; p<0.01, respectively) and sE-selectin (54.8 +/-6.9 versus 65.9 +/-8.8 ng/mL; p<0.001 and 62.6 +/-9.4 ng/mL; p=0.056, respectively). The levels of sICAM-1 were similar in all 3 groups. Multivariate analyses showed that the higher sCAM levels in patients occurred independently of lipoprotein levels. Waist circumference as a marker of abdominal adiposity was the only independent predictor of elevated concentrations of all 3 cell adhesion molecules in multivariate analyses. sE-selectin was associated with HbA1C levels (p<0.01) in diabetic men at baseline. After 12 weeks of ciprofibrate therapy, sVCAM-1 levels were reduced by 13.5 +/-2.1%, sICAM-1 levels by 11.8 +/-2.2%, and sE-selectin levels by 17.1 +/-3.5% (p<0.01 for all) with the greatest sE-selectin reduction in the diabetic subgroups (p<0.001). There was no correlation between the lowering of soluble adhesion molecules and the magnitude of lipid-lowering effect. An increased level of circulating adhesion molecules may be a mechanism by which dyslipidemia and/or diabetes mellitus promotes atherogenesis, and treatment with ciprofibrate may alter vascular cell activation.     

Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes

Aims/hypothesis Activation of the receptor for advanced glycation end products (RAGE, also known as AGE-specific receptor [AGER]) has been implicated in the development of diabetic vascular complications. Blockade of RAGE using a soluble form of the receptor (sRAGE) suppressed vascular hyperpermeability and atherosclerosis in animal models. Since little is known about the regulation of endogenous sRAGE levels, we determined whether serum sRAGE is influenced by circulating AGEs and the severity of nephropathy in type 2 diabetic patients.Materials and methods We recruited 150 healthy control and 318 diabetic subjects. Diabetic subjects were subdivided into those with proteinuria, microalbuminuria or normoalbuminuria. Serum sRAGE was assayed by ELISA and serum AGEs by competitive ELISA using a polyclonal rabbit antiserum raised against AGE-RNase.Results Diabetic subjects had higher sRAGE (1,029.5 pg/ml [766.1–1,423.0] interquartile range vs 1,002.6 [726.5–1,345.3], p<0.05) and AGEs (4.07±1.13, SD, unit/ml vs 3.39±1.05, p<0.01) than controls. Proteinuric subjects had the highest sRAGE levels and there was a significant trend between the severity of nephropathy and sRAGE (p=0.01). In diabetic subjects, serum log(sRAGE) correlated with AGEs (r=0.27, p<0.001), log(plasma creatinine) (r=0.31, p<0.001), log(urine AER) (r=0.24, p<0.01) and log(triglycerides) (r=0.15, p<0.01). On stepwise linear regression analysis, AGEs and creatinine levels were the main independent determinants of sRAGE concentration.Conclusions/interpretation Serum sRAGE levels and circulating AGEs are associated with the severity of nephropathy in type 2 diabetic patients. Prospective studies are required to determine whether endogenous sRAGE potentially influences the development of diabetic vascular complications.     

Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein

CONTEXT: The interaction of advanced glycation end products, including Nepsilon-(carboxymethyl)lysine-protein adducts (CML) and S100A12 protein, with their cellular receptor (RAGE) is implicated in the pathogenesis of diabetic vascular complications. RAGE has a circulating secretory receptor form, soluble RAGE (sRAGE), which, by neutralizing the action of advanced glycation end products, might exert a protective role against the development of cardiovascular disease. OBJECTIVE: The objective of the study was to investigate whether plasma sRAGE levels are associated with glycemic control, proinflammatory factors, or circulating ligands of RAGE such as plasma CML and S100A12 protein. STUDY DESIGN: We studied 160 subjects, 84 subjects with type 2 diabetes (aged 60 +/- 7 yr) and 76 nondiabetic controls (aged 45 +/- 10 yr). RESULTS: Plasma sRAGE was lower in diabetic patients than controls [141 (53-345) vs. 735 (519-1001) pg/ml, median (interquartile range), P < 0.0001], whereas CML levels were higher in diabetic patients than controls [67.9 (46.0-84.7) vs. 43.4 (28.0-65.0) microg/ml, P < 0.0001]. In stepwise regression analysis of the whole data set, hemoglobin A1c, insulin resistance (as homeostasis model assessment), and C-reactive protein were independently associated with plasma sRAGE, whereas age was not. In a subgroup of 26 diabetic and 24 nondiabetic subjects of similar age (54 +/- 3 yr), plasma S100A12 levels were higher in diabetic subjects [49 (39-126) vs. 28 (21-39) ng/ml]. Moreover, low sRAGE and high S100A12 were strongly associated with increased risk for cardiovascular disease (Framingham score). In this subgroup, the plasma S100A12 level was the only determinant of plasma sRAGE concentration. CONCLUSION: Plasma level of sRAGE is down-regulated in chronic hyperglycemia; among its ligands, S100A12 protein, but not CML, appears to be associated with this effect.     

Elevated plasma levels of vascular cell adhesion molecule-1 (VCAM-1) in diabetic patients with microalbuminuria: a marker of vascular dysfunction and progressive vascular disease

Advanced glycation endproducts (AGEs), which accumulate in diabetic vasculature, result in enhanced expression of endothelial cell-associated vascular cell adhesion molecule-1 (VCAM-1) as well release of a soluble form of VCAM-1 (sVCAM-1) into culture supernatants. We hypothesized that sVCAM-1 in diabetic plasma might reflect early vascular perturbation in diabetic vasculopathy. Diabetic patients with microalbuminuria, a group with a high incidence of vascular complications, had increased plasma levels of sVCAM-1, ∼1.5-fold greater than diabetic patients without microalbuminuria; P  < 0.05. sVCAM-1 may be an indicator of ongoing cellular dysfunction in diabetes, as well as a dynamic surrogate marker for the effectiveness of therapeutic interventions.     

Evidence for the regulation of levels of plasma adhesion molecules by proinflammatory cytokines and their soluble receptors in type 1 diabetes

OBJECTIVES: To investigate the regulation of soluble adhesion molecules by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and relationships with circulating cytokine receptors, in vivo, in type 1 diabetes. DESIGN: Cross-sectional study. SETTING: University hospital diabetes clinic. SUBJECTS: A total of 47 non-nephropathic, Caucasian type 1 diabetics and 39 nondiabetic controls. OUTCOME MEASURES: Plasma levels of TNF-alpha, IL-6, their soluble receptors and adhesion molecules intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and von Willebrand factor (vWF), and risk factors for cardiovascular disease. RESULTS: Plasma concentrations of IL-6 were elevated in diabetic patients compared with controls [median (interquartiles) 1.28 (0.89-2.65) vs. 0.66 (0.45-1.73) pg mL(-1): P=0.016], and in these patients IL-6 and soluble IL-6 receptor (sIL-6R) levels correlated with concentrations of sICAM-1 (r = 0.41, P = 0.012 and r = 0.31, P = 0.04, respectively). Tumour necrosis factor-alpha soluble receptor-2 (sTN-FRII), but not TNF-alpha or tumour necrosis factor soluble receptor-1 (sTNFRI), was elevated in diabetic subjects (P = 0.027). Plasma TNF-alpha levels correlated with sVCAM-1 (r = 0.39, P = 0.008), triglycerides (r = 0.36, P = 0.02 1) and diastolic blood pressure (r = 0.35; P = 0.024). Both sTNFRI and sTNFRII correlated with blood pressure (r = 0.46, P = 0.002; r = 0.32, P = 0.034) and triglycerides (r = 0.33, P = 0.033; r = 0.29, P = 0.05). In contrast, HDL-cholesterol and triglyceride were related to sE-selectin (r = -0.45 and +0.45; both P < 0.001). Neither sE-selectin nor vWF were related to cytokine concentrations. Finally, both TNF-alpha and sIL-6R correlated sTNFRI and RII (r = 0.44-0.49, P < 0.001). None of these interactions were apparent in control subjects. CONCLUSIONS: (i) IL-6, through effects on sICAM-1, and TNF-alpha via effects on sVCAM-1, may promote vascular adhesion; (ii) plasma levels of TNF-alpha are associated with dyslipidaemia and increased blood pressure, adding to vascular disease risk; (iii) the actions of both cytokines are probably modified by altered production of soluble receptors in diabetic subjects.     

Elevated soluble intercellular adhesion molecule-1 levels in patients with systemic lupus erythematosus: relation to insulin resistance

OBJECTIVE: Intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are members of the immunoglobulin supergene family and play a central role in cell-to-cell and in cell-to-extracellular matrix-mediated immune responses. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by a wide variety of immunological abnormalities. The relationship between soluble adhesion molecules and insulin resistance has been observed in different populations. However, the association of circulating levels of soluble cell adhesion molecules with insulin resistance and/or hyperinsulinemia in patients with SLE has not been extensively established. METHODS: We evaluated the relationship of soluble ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) to insulin resistance in 68 patients with SLE and 34 age-matched healthy controls. RESULTS: Patients with SLE had significantly higher fasting insulin levels, homeostasis model assessment insulin resistance (HOMA-IR), HOMA beta-cell, and plasma levels of sICAM-1 and sVCAM-1 than controls. SLE patients with HOMA-IR in the top quartile had the highest plasma levels of sICAM-1. However, there was no statistical difference in plasma levels of sVCAM-1 between patients in the respective quartiles of insulin sensitivity-related variables. Plasma levels of sICAM-1, but not sVCAM-1, were significantly correlated with fasting insulin (r = 0.327, p = 0.006), HOMA-IR (r = 0.278, p = 0.022), and HOMA beta-cell (r = 0.359, p = 0.003). In addition, fasting insulin was responsible for sICAM-1 variability in patients with SLE. CONCLUSION: The elevation of plasma levels of sICAM-1 was associated with a status of insulin resistance in patients with SLE.     

Prospective study of autonomic neuropathy as a predictor of mortality in patients with diabetes

To investigate the relationships between serum concentrations of soluble adhesion molecules and hyperglycemia, insulin resistance, or other conventional risk factors in type 2 diabetes, we measured soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), insulin sensitivity, and conventional risk factors in 150 Japanese type 2 diabetic patients without apparent diabetic macroangiopathy. High serum concentrations of sVCAM-1 and sE-selectin were observed in patients with type 2 diabetes. Serum concentrations of soluble adhesion molecules were not significantly influenced by sex, hypertension, dyslipidemia, or microangiopathy. Spearman correlation showed that sVCAM-1 concentrations correlated significantly with fasting plasma glucose (FPG), fasting C-peptide, and insulin sensitivity [K index of the insulin tolerance test (K(ITT))] (rho=0.19,0.23, and -0.23, respectively). Soluble E-selectin concentrations correlated significantly with body mass index (BMI), FPG, fasting C-peptide, insulin sensitivity, and triglyceride (rho=0.33,0.42,0.26,-0.48, and 0.29, respectively). Multiple regression analysis showed that FPG, fasting C-peptide, and total cholesterol were independent factors that correlated with sVCAM-1 levels. BMI, FPG, and insulin sensitivity were independent factors that correlated with sE-selectin levels. Serum concentrations of sE-selectin significantly increased associated with clustering of conventional risk factors those obesity, hypertension, dyslipidemia, and current smoking (P<0.01). Thus, sVCAM-1 and sE-selectin levels are related to both hyperglycemia and insulin resistance. Soluble E-selectin levels may be related to obesity, hyperglycemia, and insulin resistance and may reflect the presence of a multiple risk factor clustering syndrome.     

Positive association of serum levels of advanced glycation end products and high mobility group box–1 with asymmetric dimethylarginine in nondiabetic chronic kidney disease patients

There is accumulating evidence that engagement of the receptor for advanced glycation end products (RAGE) with ligands such as advanced glycation end products (AGEs) and high mobility group box–1 (HMGB-1) elicits vascular inflammation, thus contributing to the increased risk for cardiovascular disease. Furthermore, enhanced accumulation of asymmetric dimethylarginine (ADMA) plays a role in cardiovascular disease in chronic kidney disease (CKD) patients. However, the relationships among serum levels of AGEs, HMGB-1, soluble form of RAGE (sRAGE), and ADMA are largely unknown. The aim of the present study is to determine their relationships in CKD patients. Twenty nondiabetic normotensive CKD patients with dyslipidemia and 20 age- and sex-matched healthy controls were enrolled. All subjects underwent determination of blood chemistries; urinary proteinuria; and serum levels of AGEs, HMGB-1, sRAGE, and ADMA. Serum AGE, HMGB-1, sRAGE, and ADMA levels in CKD patients were significantly higher than those in control subjects. Circulating levels of AGEs in CKD patients were positively associated with sRAGE and ADMA, and HMGB-1 with ADMA, but not sRAGE. There were no significant associations among these markers and serum creatinine, estimated glomerular filtration rate, proteinuria, and lipid levels. In multiple regression analyses, AGEs and HMGB-1 were independently correlated with ADMA. The present study demonstrated that AGE and sRAGE levels were correlated with each other and that AGEs and HMGB-1 were independently associated with ADMA in nondiabetic CKD patients. Elevation of the RAGE ligands may enhance ADMA levels, suggesting the active involvement of AGE/HMGB-1–RAGE–ADMA axis in CKD patients.     

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.     

Circulating soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in immunocompetent and renal transplant patients: correlation with cytomegalovirus disease and renal function.

The plasma levels of the soluble adhesion molecules, soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1), were measured before and after transplantation in 26 renal transplant recipients, and in 173 longitudinally collected samples in 17 of the patients. The patients were carefully monitored for the presence of cytomegalovirus (CMV) infection and rejection. Forty healthy blood donors and 12 otherwise healthy subjects with symptomatic primary CMV infections served as controls. During CMV disease, plasma levels of sVCAM-1 and sICAM-1 were elevated in both renal transplant patients and otherwise healthy subjects with CMV disease. The sVCAM-1 levels were strongly elevated before transplantation in renal transplant recipients and correlated with creatinine levels. Increased sVCAM-1 levels were also registered during rejection episodes. CMV disease, per se, is associated with markedly increased levels of sVCAM-1 and sICAM-1. There is also a correlation of sVCAM-1 levels with serum creatinine levels. Thus, the presence of CMV infection and renal function are factors that must be considered in further studies of soluble adhesion molecules.     

系统性红斑狼疮患者血清可溶性黏附分子的检测

目的检测系统性红斑狼疮(SLE)患者血清黏附分子中可溶性血管细胞黏附分子-1(sVCAM-1)、可溶性细胞间黏附分子-1(sICAM-1)的水平,并探讨其临床意义。方法采用酶联免疫吸附试验(ELISA)法,检测30名健康人和60例SLE患者血清sVCAM-1、sICAM-1水平,以分析其与SLE活动性变化关系。结果①SLE患者血清sVCAM-1平均水平为2342ng/ml,显著高于正常人对照组1240ng/ml(P<0.001)。②SLE患者中血清sICAM-1平均水平为802ng/ml,显著高于正常人对照组626ng/ml(P<0.001)。③SLE患者中,血清sVCAM-1水平活动期高于稳定期(P<0.05),sICAM-水平活动期高于稳定期(P<0.05)。④SLE组血清sVCAM-1和sICAM-1水平与SLE病情活动指数(SLEDAI)、抗dsDNA抗体水平及尿蛋白的发生呈正相关,与血清补体C3水平呈负相关。结论sVCAM-1,sICAM-1可能参与SLE发病机制。     

The effect of cigarette smoking on soluble adhesion molecules in middle-aged patients with Type 2 diabetes mellitus.

AIMS: To investigate the effect of smoking on soluble adhesion molecules in middle-aged diabetic patients. METHODS: One hundred out-patients with Type 2 diabetes and 100 age- and sex-matched non-diabetic subjects without clinical macrovascular disease were selected. Soluble serum levels of adhesion molecules were analysed using enzyme immunoassay. Carotid atherosclerosis was assessed using an ultrasound system. RESULTS: When compared with non-diabetic subjects, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and sE-selectin were found at significantly high levels in diabetic patients and significantly higher levels of sICAM-1, sE-selectin, and sP-selectin were observed in current smokers than never-smokers among diabetic or non-diabetic subjects, respectively. The combined, but not enhanced, effects of diabetes mellitus and smoking were observed in sICAM-1 and sE-selectin levels. Additionally, levels of sICAM-1 (P < 0.05) and sE-selectin (P < 0.01), but not sP-selectin, were high in ex-smokers when compared with never-smokers among diabetic patients. Diabetic smokers were also found to have marked carotid atherosclerosis, which was related to increased levels of sICAM-1. CONCLUSIONS: Our present study shows that levels of adhesion molecules were higher in diabetic smokers than diabetic non-smokers or non-diabetic smokers, and that cessation after chronic smoking did not restore the levels of sICAM-1 and sE-selectin, though sP-selectin levels were restored. These data suggest a possible mechanism for accelerated atherosclerosis induced by smoking in patients with diabetes.     

Plasma levels of soluble cellular adhesion molecules in patients with arterial hypertension. Correlations with plasma endothelin-1

Background: Several reports have shown that circulating, soluble cellular adhesion molecules and endothelin-1 (ET-1) are implicated in the pathophysiological events of atherosclerosis and may reflect the endothelial dysfunction characterizing this disorder. Methods: To evaluate the expression of these factors in arterial hypertension (AH), we measured plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble P-selectin (sP-selectin), and ET-1 in 60 untreated patients with mild to moderate AH (hypercholesterolemic: n=31, normocholesterolemic: n=29) and 30 sex- and age-matched normocholesterolemic normotensive controls. Results: Hypertensive patients exhibited significantly higher levels of sICAM-1 (234+/-21 vs. 187+/-12 ng/ml, P<0.005), sVCAM-1 (681+/-42 vs. 589+/-23 ng/ml, P<0.005), sP-selectin (89+/-17 vs. 55+/-11 ng/ml, P<0.01) and ET-1 (6.2+/-0.7 vs. 2.4+/-0.3 pg/ml, P<0.01) than did normotensive controls. The normocholesterolemic hypertensives had lower levels of sICAM-1, sVCAM-1 (P<0.01), sP-selectin and ET-1 (P<0.05) than hypercholesterolemic hypertensives, but higher levels than normotensive controls (P<0.05). In hypertensives, plasma ET-1 was significantly correlated with mean arterial pressure (r=0.51, P<0.03) and sICAM-1 levels (r=0.64, P<0.01). In hypercholesterolemic hypertensives, LDL cholesterol was also significantly correlated with plasma levels of sICAM-1 (r=0.53, P<0.04) and sP-selectin (r=0.41, P<0.05). Conclusions: Plasma levels of soluble cellular adhesion molecules are elevated in hypertensive patients in comparison to normotensive controls and may be related to plasma ET-1 activity. The coexistence of hypercholesterolemia may enhance the plasma soluble adhesion molecule activity induced by AH.     

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.     

Relationship of soluble RAGE and RAGE ligands HMGB1 and EN-RAGE to endothelial dysfunction in type 1 and type 2 diabetes mellitus

Receptor for advanced glycation end-products (RAGE) plays the essential role in the pathogenesis of diabetic vascular complications. The aim of the study was to compare concentration of soluble RAGE and its ligands (EN-RAGE and HMGB1) with different biochemical parameters in Type 1 (T1DM) and Type 2 (T2DM) diabetes mellitus.Total number of 154 persons (45 T1DM, 68 T2DM, 41 controls) was examined and concentrations of sRAGE, EN-RAGE and HMGB1 were measured and compared to diabetes control, albuminuria, cell adhesion molecules and metalloproteinases (MMPs).Mean serum sRAGE concentration was higher in T1DM as compared to controls (1137±532 ng/l vs. 824±309 ng/l, p<0.01). Similarly, EN-RAGE was significantly higher in both diabetic groups (p<0.001) and HMGB1 concentrations were elevated in T2DM patients (p<0.01). Significant relationship was found between MMP9 and HMGB1 and EN-RAGE in diabetic patients. Inverse relationship was observed between MMP2 and MMP9 in both types of diabetic patients (r= - 0.602, p<0.002 and r= - 0.771, p<0.001). Significant positive correlation was found between sRAGE and ICAM-1, VCAM-1 or vWF (p<0.01 to p<0.001).We conclude that serum sRAGE and RAGE ligands concentrations reflect endothelial dysfunction developing in diabetes.