Increased soluble E-selectin levels in type 2 diabetic patients with peripheral arterial disease.

AIM: Abnormal endothelial function is well known in patients with type 2 diabetes mellitus and thought to induce macroangiopathy. Increased levels of adhesion molecules have been found in type 2 diabetic patients and it has been suggested that they play an important role in the initiation of atherosclerosis. The aim of the present study was to clarify the relationship between objectively proven peripheral arterial disease (pAVD) and serum levels of soluble adhesion molecules in patients with type 2 diabetes mellitus. METHODS: Levels of soluble E-selectin, ICAM-1 and VCAM-1 were evaluated in 18 type 2 diabetic patients with pAVD assessed by Doppler ultrasound, in 19 type 2 diabetic patients and 22 non-diabetic subjects without pAVD. RESULTS: Soluble E-selectin levels were significantly increased in pAVD-diabetic patients compared to diabetics and non-diabetics without pAVD (78.7+/-29 vs 49.7+/-20.4 and 36+/-17 ng/ml respectively, p<0.001), while sICAM-1 and sVCAM-1 levels were comparable between the groups. No significant correlation was found between pAVD and adhesion molecule levels. Peripheral AVD was correlated with smoking (p=0.024), duration of diabetes (p=0.048) and microalbuminuria (p=0.041). Regression analysis revealed that only smoking (R=0.536, p=0.012) and glycosylated hemoglobin (R=0.435, p=0.036) were independent factors related to pAVD. Soluble ICAM-1 levels were significantly higher (p=0.041) in diabetic smokers with pAVD and sVCAM-1 (p=0.011) in patients with longer duration of diabetes. CONCLUSION: Type 2 diabetic patients with pAVD showed increased serum sE-selectin levels. No significant relationship was found between the presence or extent of pAVD and measured adhesion molecules. Our results suggest that sE-selectin reflects endothelial activation and is possibly involved in the atherogenesis process with the contribution of other factors that characterize the metabolic syndrome of diabetes.     

Patients with essential hypertension present higher levels of sE-selectin and sVCAM-1 than normotensive volunteers

In essential hypertension (EH) patients, blood pressure can modify serum concentrations of some soluble forms of cell adhesion molecules (CAM), e.g., soluble E-selectin (sE-selectin) and soluble vascular cell adhesion molecule-1 (sVCAM-1). The objective of this study was to compare the serum levels of these CAMs in compensated (CH) and non-compensated (NCH) EH patients. Our findings show that sE-selectin and sVCAM-1 levels are higher in EH patients than normotensive subjects (sVCAM-1: 796+/-52 vs. 605+/-24 ng/mL, p<0.0001, and sE-selectin: 71+/-21 vs. 48+/-14 ng/mL, p<0.0001). Serum concentrations of both CAMs was higher in NCH patients than CH patients. High arterial blood pressure (ABP) may therefore increase the production of cell adhesion molecules, probably through endothelial activation.     

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.     

Relationship between insulin resistance, soluble adhesion molecules, and mononuclear cell binding in healthy volunteers.

The relationship between insulin resistance, soluble adhesion molecules E-selectin (sE-selectin), intracellular adhesion molecule-1 (sICAM-1), and vascular adhesion molecule-1 (sVCAM-1), mononuclear cell binding to cultured endothelium, and lipoprotein concentrations were evaluated in 28 healthy, nondiabetic, and normotensive individuals. The mean (+/-SEM) lipid and lipoprotein concentrations were within the normal rage: cholesterol (199 +/- 18 mg/dL); triglyceride (128 +/- 12 mg/dL); low-density cholesterol (127 +/- 8 mg/dL; and high-density cholesterol (47 +/- 3 mg/dL). The results indicated that degree of insulin resistance was significantly correlated with concentrations of sE-selectin (r = 0.54, P < 0.005), sICAM-1 (r = 0.67, P < 0.001), and sVCAM-1 (r = 0.41, P < 0.05). Furthermore, the relationship between insulin resistance and both sE-selectin and sI-CAM-1 remained statistically significant when adjusted for differences in age, gender, body mass index, and all measures of lipoprotein concentrations. Finally, mononuclear cell binding correlated significantly with concentrations of sE-selectin (r = 0.54, P < 0.005) and sICAM-1 (r = 0.47, P < 0.01). These findings raise the possibility that previously described relationships between soluble adhesion molecules in patients with hypertension, type 2 diabetes, and dyslipidemia may be due to the presence of insulin resistance in these clinical syndromes and suggests that insulin resistance may predispose individuals to coronary heart disease by activation of cellular adhesion molecules.     

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.     

Soluble adhesion molecules are not involved in the development of retinopathy in type 2 diabetic patients

Abstract. Raised serum levels of adhesion molecules are believed to reflect endothelial activation and may contribute to the development of diabetic vascular complications. The aim of this study was to clarify the association between soluble adhesion molecules levels and retinopathy in type 2 diabetic patients. Levels of soluble Eselectin, ICAM-1 and VCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA) in 47 type 2 diabetic patients classified in two subgroups according to the presence (n=34) or absence (n=13) of retinopathy as determined by fundus ophthalmoscopy; 22 control subjects were also studied. Soluble E-selectin levels were significantly elevated in both diabetic subgroups compared to control subjects (p<0.01), while no significant difference was found in sICAM-1 and sVCAM-1 levels. However, sE-selectin, sICAM-1 and sVCAM-1 levels were comparable in diabetic subgroups. The progression of retinopathy was not associated with an increase in soluble adhesion molecules levels. Stepwise multiple regression analysis revealed that only diabetes duration and microalbuminuria were independent determinants of retinopathy (p<0.01). Our results confirm the contribution of endothelial activation in the development of diabetic complications as indicated by increased levels of soluble adhesion molecules. However, a direct implication of adhesion molecules in the pathogenesis or progression of type 2 diabetic retinopathy cannot be supported.     

Effects of efonidipine on platelet and monocyte activation markers in hypertensive patients with and without type 2 diabetes mellitus

We compared the levels of microparticles, platelet activation markers, soluble cell adhesion molecules, and soluble selectins between hypertensive patients with and without type 2 diabetes and control subjects. Binding of anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib monoclonal antibodies to platelets did not differ significantly between the hypertensive patients and controls, but platelet expression of activation markers (CD62P, CD63, PAC-1, and annexin V) was higher in the hypertensive patients. Platelet-derived microparticle (PDMP) and monocyte-derived microparticle (MDMP) levels were significantly higher in the hypertensive patients than in the controls. Soluble ICAM-1, VCAM-1, P-selectin, and E-selectin levels were also higher in the hypertensive patients, and they were significantly higher in the hypertensive patients with diabetes. After treatment with efonidipine, the levels of PDMPs, CD62P-, CD63-, PAC-1-, and annexin V-positive platelets, sICAM-1, sVCAM-1, sP-selectin, and sE-selectin all decreased significantly. The MDMP levels decreased, and the decrease was significant in the hypertensive patients with diabetes. These findings suggest that administration of efonidipine to hypertension patients with diabetes may prevent the development of cardiovascular complications caused by cell adhesion molecules or activated platelets and monocytes.     

Altered levels of soluble adhesion molecules in patients with rheumatoid arthritis complicated by peripheral neuropathy

OBJECTIVE: To assess levels of 2 circulating soluble adhesion molecules, vascular cellular adhesion molecule (sVCAM) and E-selectin, in patients with rheumatoid arthritis (RA) complicated by peripheral neuropathy compared to RA patients with no neurological complications and healthy controls. METHODS: In total, 25 RA patients with peripheral neuropathy (detected by clinical examination and confirmed by electromyography and nerve conduction studies), 40 RA patients without peripheral neuropathy, and 25 controls were studied. Clinical and laboratory assessments of disease activity were carried out and levels of sVCAM-1 and E-selectin were measured by ELISA in each of the 3 groups. RESULTS: Levels of sVCAM-1 and sE-selectin were higher (p < 0.001) in RA patients with peripheral neuropathy than in patients without neuropathy and controls. Levels of sE-selectin and sVCAM-1 correlated positively with disease activity variables. Correlation was independent of age and sex. CONCLUSION: Peripheral neuropathy in patients with RA is associated with increased endothelial cell activation evidenced by elevated serum levels of sVCAM-1 and sE-selectin in this group of patients.     

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.     

Circulating E-selectin,vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in men with coronary artery disease assessed by angiography and disturbances of carbohydrate metabolism

It is hypothesized that adhesion molecules could be an early predictor of coronary artery disease. Therefore we investigated the relationship between the concentrations of soluble forms of adhesion molecules and disturbances of glucose metabolism in 78 men referred for coronary angiography but with no previous history of diabetes. The group consisted of 78 men (mean age, 47.6 +/- 7.0 years; mean body mass index [BMI], 28.4 +/- 3.24 with the symptoms of angina pectoris and positive exercise test. All subjects were given a standard oral glucose tolerance test (OGTT) with glucose and insulin estimations. Fasting plasma concentrations of the soluble (s) forms of E-selectin, intercellular adhesion cell molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and HbA(1c) were also measured. According to the OGTT, 10.2% of the patients (n = 8) fulfilled the criteria for type 2 diabetes mellitus and 44.9% (n = 35) for impaired glucose tolerance (IGT). The highest concentrations of sE-selectin were observed in patients with type 2 diabetes mellitus and were significantly higher in comparison to the group with normal glucose tolerance and IGT. The concentration of sVCAM-1 increased with the progression of disturbances of glucose metabolism and remained the highest in type 2 diabetic patients. sICAM-1 concentration was not significantly different. sE-selectin concentration correlated significantly with fasting glucose (r = 0.23, P =.041), postload glucose (r = 0.39, P =.001), and postload insulin (r = 0.28, P =.023). sVCAM-1 was significantly related to the postload glucose concentration (r = 0.30, P =.009). A significant correlation between sICAM-1 concentration and postload insulin was also observed (r = 0.27, P =.025). This would suggest that hyperglycemia increases sE-selectin and sVCAM-1 in plasma, which reflects excessive formation of atherosclerotic plaques in patients with disturbances of glucose metabolism.     

Circulating adhesion molecules in allergic and non-allergic asthma

Circulating forms of adhesion molecules (intercellular-adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin ) are related to the turnover of these molecules on the cell surface. In contrast to the other molecules, the levels of E-selectin probably exclusively reflect the activity of endothelial cells. The aim of this study was to compare levels of circulating adhesion molecules in patients with allergic (AA) and non-allergic asthma (NA) and to relate the levels of soluble adhesion molecules to methacholine responsiveness and lung function. The study comprised 19 patients with AA, 15 patients with NA and 17 healthy subjects. Soluble adhesion molecules, spirometry, methacholine responsiveness and peak flow variability was measured. The group of patients with AA had higher levels of sE-selectin than the reference group (P=0.046). Serum levels of sE-selectin correlated significantly with bronchial responsiveness (r=0.76) and peak flow variability (r=0.75) (P<0.01) in the NA but not in the AA group. All adhesion molecules in AA (P<0.05-<0.001), but only sE-selectin in NA (P<0.05), were correlated to airway conductance. sVCAM-1 was reduced by inhaled steroids (P<0.01). Our results indicate that endothelial cells are activated in asthma and that this activity has a bearing on airflow variability and bronchial responsiveness in NA.     

Losartan and Simvastatin Inhibit Platelet Activation in Hypertensive Patients

Background: Diabetic patients also show hypercoagulability and platelet hyperaggregability, with increased levels of platelet activation-markers such as P-selectin (CD62P) and platelet-derived microparticles. We investigated the effects of losartan and simvastatin on circulating levels of platelet activation markers, microparticles, soluble selectins, and soluble cell adhesion molecules in hypertensive and hyperlipidemic patients with or without Type 2 diabetes. Methods: The subjects included 25 normotensive healthy controls and 41 hypertensive patients. The 41 hypertensive patients were divided into three groups: group A had hypertension and hyperlipidemia (n = 11), group B had hypertension and Type 2 diabetes (n = 14), and group C had hypertension, hyperlipidemia, and diabetes (n = 16). Losartan was administered to all of the patients at a dose of 50 mg/day for 24 weeks. In addition, simvastatin was administered to the hyperlipidemic patients at a dose of 10 mg/day for 24 weeks. Results: There were significant differences in the levels of CD62P, CD63, PAC-1, platelet microparticles, endothelial microparticles, sE-selectin, and sVCAM-1 between the hypertensive patients and healthy controls. These markers were all significantly increased in hypertensive and hyperlipidemic patients with Type 2 diabetes. In hypertensive patients with diabetes, CD62P, CD63, PAC-1, platelet and endothelial microparticles, and soluble adhesion markers were all decreased by losartan monotherapy. The decrease of each marker in hypertensive and hyperlipidemic patients given combined therapy with losartan plus simvastatin was greater among those with than without Type 2 diabetes. Low-density lipoprotein was decreased significantly by simvastatin and was correlated with CD62P or platelet microparticles in all of the patients. Conclusion: Administration of losartan plus simvastatin to hypertensive and hyperlipidemic patients with Type 2 diabetes may prevent the development of cardiovascular complications caused by activated platelets and microparticles via another mechanism in addition to reduction of the blood pressure or lipid levels.This revised version was published online in May 2005 with a corrected cover date.     

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.     

Neutrophil surface expression of CD11b and CD62L in diabetic microangiopathy

The aims of the study are (1) assessment of cell surface expression of adhesion molecules CD11b and CD62L on peripheral blood neutrophils in patients with type 2 diabetes and microangiopathy; (2) analysis of serum levels of soluble adhesion molecules: E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and von Willebrand factor (vWF) and; (3) evaluation of systemic inflammatory markers like interleukin-6 (IL-6), soluble interleukin-6 receptor (IL-6Rs), high sensitivity C-reactive protein (hsCRP) and fibrinogen. Thirty patients with type 2 diabetes and microangiopathy were enrolled in the study. The study group was compared to 22 patients with type 2 diabetes without microangiopathic compliations. The control group included 20 healthy volunteers. Flow cytometry was used to analyse surface expression of adhesion molecules. Both inflammatory markers and soluble adhesion molecules were determined by immunoenzymatic assay. A significant increase in neutrophil surface CD11b expression (P < 0.01) as well as decrease in surface CD62L expression (P < 0.01) were observed in the group with diabetic microangiopathy in comparison with diabetic group without microangiopathic complications and healthy controls. Moreover, significantly higher concentrations of sICAM-1 (P < 0.05), sVCAM-1 (P < 0.05), sE-selectin (P < 0.05), vWF (P < 0.01), hsCRP (P < 0.01), IL-6 (P < 0.01) and fibrinogen (P < 0.001) were also found in patients with microangiopathy in comparison with the control group. IL-6Rs concentrations did not significantly vary between groups. We concluded (1) diabetic microangiopathy is accompanied by increase in CD11b expression and decrease in CD62L expression on peripheral blood neutrophils; (2) in diabetic microangiopathy rise in CD11b expression indicates neutrophil activation and intensified adhesion; (3) the development of diabetic microangiopathy is accompanied by an increase in soluble adhesion molecules and inflammatory markers concentrations in the blood.     

High serum concentrations of soluble E-selectin in patients with impaired glucose tolerance with hyperinsulinemia

High serum concentrations of soluble adhesion molecules are present in diabetics, but whether similar levels are present in patients with impaired glucose tolerance (IGT) is unclear. We measured serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and sE-selectin in 128 nondiabetic Japanese subjects. The concentrations of sICAM-1, sVCAM-1, and sE-selectin in IGT patients (n=47) were not different from those in subjects with normal glucose tolerance (NGT; n=81). IGT patients were subdivided into two groups by the results of 75 g OGTT, those with low- (hypoinsulinemia; n=23) or high-insulin (hyperinsulinemia; n=24). The levels of sICAM-1 and sVCAM-1 were not different among NGT and IGT with high-insulin or with low-insulin. However, sE-selectin concentrations were significantly higher in IGT patients with high-insulin than in NGT and IGT with low-insulin (61.1+/-3.4, 47.1+/-1.8 and 43.7+/-3.9 ng/ml, respectively, P<0.001). Adjustment for age and gender did not influence the results. Serum sE-selectin concentrations correlated significantly with the area under the curve of insulin (AUC(insulin)), AUC(glucose), diastolic blood pressure, and triglyceride levels (r=0.35, 0.26, 0.18 and 0.21, respectively), and negatively with HDL-cholesterol levels (r=-0.20). Multiple regression analysis showed that AUC(insulin) was the only independent factor that correlated with sE-selectin levels (P<0.001). Our results indicate that hyperinsulinemia/insulin resistance may be responsible for the elevation of sE-selectin levels.     

Low-density lipoprotein (LDL)-induced monocyte-endothelial cell adhesion, soluble cell adhesion molecules, and autoantibodies to oxidized-LDL in chronic renal failure patients on dialysis therapy

Premature atherosclerosis is a major cause of morbidity and mortality in chronic renal failure patients undergoing dialysis. In this study, we compared autoantibodies to oxidized low-density lipoprotein (OX-LDL), soluble cell adhesion molecules (CAMs), and the effect of both LDL and OX-LDL on monocyte endothelial cell adhesion in chronic renal failure patients on hemodialysis (HD, n = 16) and peritoneal dialysis (PD, n = 17) compared with matched healthy control subjects (C, n = 17). In addition, we studied the effect of supplementation with RRR-alpha-tocopherol (AT) 800 IU/d for 12 weeks on the above measures. LDL and OX-LDL induced adhesion of U937 cells to cultured endothelium, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), and soluble E-selectin (sE-selectin); autoantibodies to OX-LDL and markers of lipid peroxidation were determined before and after AT supplementation. Native LDL from PD patients induced greater monocyte-endothelial cell adhesion than LDL from C subjects (43.8% +/- 17.0% v25.3% +/- 17.7%, respectively, P = .0028). OX-LDL from chronic renal failure patients on both PD and HD stimulated greater adhesion than OX-LDL from the C subjects (68.0% +/- 18.5% and 57.6% +/- 15.1% v 40.9% +/- 17.3%, respectively, P < .01); OX-LDL from PD patients induced greater adhesion than that from HD patients (P < .01). Plasma methylglyoxal levels were significantly increased in both HD and PD groups, with higher levels in the HD group. Chronic renal failure patients on HD and PD also had higher levels of plasma sVCAM-1 and sE-selectin than C subjects (P < .01), indicating endothelial activation. Titers of autoantibodies to OX-LDL were not elevated in renal failure patients. Supplementation with AT 800 IU/d for 12 weeks, while resulting in significant enrichment with AT in LDL, did not have a significant effect on any of the parameters studied. This study makes the novel observation that the LDL of chronic renal failure patients on HD and PD appears to be potentially more atherogenic, since it induces greater monocyte-endothelial cell adhesion.     

Soluble E-selectin in essential hypertension: a correlate of vascular structural changes

BACKGROUND: Increased expression of the endothelial leukocyte adhesion molecule E-selectin is implicated in vascular disease and may accompany the development of hypertension. We evaluated plasma soluble (s) E-selectin to assess its relationship with endothelium-dependent and endothelium-independent vasodilation in patients with hypertension. METHODS: Thirty-one previously untreated and uncomplicated essential hypertensive patients were compared with 16 normotensive controls for changes in forearm blood flow (by strain-gauge plethysmography) in response to brachial artery infusion of the endothelium-dependent vasodilator acetylcholine, and of the endothelium-independent vasodilator sodium nitroprusside. As an index of structural changes, minimal forearm vascular resistances were calculated as the ratio between maximal vasodilation after 13 min of ischemia and mean blood pressure. RESULTS: Responses to acetylcholine were significantly lower and minimal forearm vascular resistances higher in hypertensives versus controls, whereas responses to nitroprusside were comparable. Baseline sE-selectin concentrations were (mean +/- SEM) 37.4 +/- 1.8 ng/mL in hypertensives and 27.8 +/- 0.7 ng/mL in normotensives (P < .001). In essential hypertensive patients, a significant (P < .01) correlation with the response to nitroprusside (r = -0.47) was found, but not with the response to acetylcholine or minimal forearm vascular resistances. sE-selectin was also positively correlated with age and LDL cholesterol. At multivariate analysis, sE-selectin remained significantly correlated with nitroprusside responses and LDL cholesterol. CONCLUSIONS: In patients with essential hypertension, plasma levels of sE-selectin are higher than in normotensive controls and mostly related to structural vascular changes.     

Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with Type 1 diabetes mellitus with microalbuminuria and overt nephropathy.

AIMS: Elevated urinary albumin excretion is associated with macrovascular atherosclerotic complications in Type 1 diabetes mellitus. Adhesion molecules mediate leucocyte adhesion to the endothelium early in the atherosclerotic process. The present study tests the hypothesis that microalbuminuria and diabetic nephropathy are associated with elevated plasma concentrations of soluble vascular adhesion molecule (sVCAM)-1, soluble intercellular adhesion molecule (sICAM)-1, and soluble E-selectin (sE-selectin) aiming to illustrate factors of potential pathogenetic relevance for the excess cardiovascular disease in diabetic patients with renal complications. METHODS: Soluble adhesion molecule concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in healthy controls (n = 16) and in 59 Type 1 diabetic patients: group 1-patients with normoalbuminuria (n = 16); group 2-patients with microalbuminuria (n = 15); group 3-patients with macroalbuminuria and normal serum creatinine (n = 15), group 4-patients with macroalbuminuria and moderately elevated serum creatinine (n = 13). RESULTS: Plasma concentrations of sVCAM-1 and sICAM-1 were similar in healthy controls and normoalbuminuric Type 1 diabetic patients, but the concentrations were increased by the presence of microalbuminuria and overt nephropathy (P < 0.001 and P < 0.0001, ANOVA). Concentrations of sE-selectin did not differ between diabetic patients and controls. CONCLUSIONS: Plasma concentration of sICAM-1 is elevated in Type 1 diabetic patients with microalbuminuria and the concentrations of sICAM-1 as well as sVCAM-1 are elevated in patients with macroalbuminuria and normal s-creatinine. The elevated plasma concentrations of these soluble adhesion molecule concentrations in patients with renal complication can be of pathogenetic importance for the development of atherosclerosis and plasma soluble adhesion molecule concentrations may provide additional information on cardiovascular risk.     

Circulating adhesion molecules in sera of asthmatic children

Infiltration of cells into the lung in asthma is regulated by several expressions of cell adhesion molecules (CAMs) on cells present in the airways, and may play a role in the pathogenesis of bronchial asthma. We sought to evaluate the role of serum concentrations of the soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and E-selectin (sE-selectin) in the control of disease activity in acute asthma. Circulating levels of sICAM-1, sVCAM-1, and sE-selectin in sera from 15 normal control subjects and from 20 allergic asthmatic children with acute exacerbations who had returned to stable condition were determined by using commercially available enzyme-linked immunosorbent assay kits. The mean concentration of serum sICAM-1 levels was significantly higher during an acute exacerbation of asthmatic children than in those with stable asthma (19.41 +/- 10.65 ng/mL vs. 13.46 +/- 5.44 ng/mL; P < 0.001) or in control subjects (9.83 +/- 2.02 ng/mL; P < 0.001). For sVCAM-1 and sE-selectin, the mean serum concentration of sVCAM-1 was slightly higher in children during an acute exacerbation asthma than when stable. However, the differences did not reach statistical significance. The mean serum concentrations of sVCAM-1 and sE-selectin in acute asthma or stable asthma were significantly higher than in control subjects. This study provides further evidence that serum concentrations of sICAM-1, sVCAM-1, and sE-selectin are increased in acute asthma. These findings further confirm that leukocyte endothelial adhesion plays a role in inflammatory airway disease.     

Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality

Endothelial cell adhesion molecules orchestrate the recruitment and binding of inflammatory cells to vascular endothelium. With endothelial dysfunction and vascular injury, the levels of endothelial bound and soluble adhesion molecules increase. Such expression is modulated by nitric oxide (NO), and in patients with sickle cell disease (SCD), these levels are inversely associated with measures of NO bioavailability. To further evaluate the role of endothelial dysfunction in a population study of SCD, we have measured the levels of soluble endothelium-derived adhesion molecules in the plasma specimens of 160 adult patients with SCD during steady state. Consistent with a link between endothelial dysfunction and end-organ disease, we found that higher levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were associated with markers indicating renal dysfunction and hepatic impairment. Analysis of soluble intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and sP-selectin levels indicated partially overlapping associations with sVCAM-1, with an additional association with inflammatory stress and triglyceride levels. Importantly, increased soluble adhesion molecule expression correlated with severity of pulmonary hypertension, a clinical manifestation of endothelial dysfunction. Soluble VCAM-1, ICAM-1, and E-selectin were independently associated with the risk of mortality in this cohort. Our data are consistent with steady state levels of soluble adhesion molecules as markers of pulmonary hypertension and risk of death.