Enhanced soluble CD40L in patients with the metabolic syndrome: relationship with in vivo thrombin generation

Angelico, Francesco; Alessandri, C.; Ferro, Domenico; Pignatelli, Pasquale; Ben, Maria Del; Fiorello, S.; Cangemi, Roberto; Loffredo, Lorenzo

doi:10.1007/s00125-006-0222-7

Cited by 41 publications

(32 citation statements)

References 39 publications

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“…Our data support the opinion that obesity is a chronic subclinical inflammatory disease as reflected by levels of WBC, hsCRP and sCD40L. 7,8,49,50 The association of leukocyte count with BMI, hsCRP and sCD40L suggests that the leukocyte count may be of clinical value as a marker of low-grade systemic inflammation in obese patients. The leukocyte count has been reported previously as a marker of inflammation and cardiovascular disease risk.…”

Section: Discussionsupporting

confidence: 85%

The Levels of Soluble CD40 Ligand and C-Reactive Protein in Normal Weight, Overweight and Obese People

Ünek

Bayraktar²,

Solmaz³

et al. 2010

Clinical Medicine & Research

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Objective: Obesity has been suggested as an independent risk factor for cardiovascular disease. Increasing evidence shows that engagement of soluble CD40 ligand (sCD40L) with its receptor plays a crucial role in the pathogenesis of atherosclerosis. The aim of the present study was to test whether obesity is associated with low-grade systemic inflammation as measured by serum high-sensitive C-reactive protein (hsCRP) and sCD40L concentration.Methods: Serum hsCRP and sCD40L concentrations were measured in 148 nondiabetic people. The participants were divided into three groups depending upon their body mass index (BMI) levels: Group 1 (normal weight), BMI<25 kg/m 2 ; Group 2 (overweight), BMI 25 kg/m 2 to 29.9 kg/m 2 ; and Group 3 (obese), BMI≥30 kg/m 2 .Results: Obese people had more elevated hsCRP levels than both their normal weight and overweight counterparts (P=0.000 and P=0.000, respectively). Similarly, serum concentrations of sCD40L were significantly higher, statistically, in obese subjects compared with normal weight subjects (P=0.003). In addition, obese subjects had higher values of sCD40L than overweight subjects, but the difference did not reach statistical significance (P=0.063). The levels of high-density lipoprotein cholesterol were significantly lower in obese subjects compared to normal weight subjects (P=0.048). The analysis of platelet count disclosed a statistically significant difference between obese subjects and normal weight subjects (P=0.028). The levels of BMI were positively correlated with the serum levels of hsCRP and sCD40L in all subjects (r=0.514, P=0.000 and r=0.283, P=0.000, respectively). Levels of hsCRP were positively correlated with waist circumference, fasting glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, leukocytes, platelets, systolic and diastolic blood pressure. Similarly, soluble CD40L levels were positively correlated with waist circumference, fasting glucose and leukocytes. Conclusion:Obese patients showed a significant increase of hsCRP and sCD40L levels compared with normal weight subjects, which might contribute to the known proinflammatory milieu found in these patients.

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Section: Discussionsupporting

confidence: 85%

The Levels of Soluble CD40 Ligand and C-Reactive Protein in Normal Weight, Overweight and Obese People

Ünek

Bayraktar²,

Solmaz³

et al. 2010

Clinical Medicine & Research

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“…For these reasons, sCD40L was chosen as the platelet activation marker in the current study. Importantly, a similar increase in sCD40L release correlated with thrombin formation has been reported in patients with the metabolic syndrome (24).…”

Section: Short-term Outcomessupporting

confidence: 78%

Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome

et al. 2008

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OBJECTIVE -Acute hyperglycemia on admission for acute coronary syndrome worsens the prognosis in patients with and without known diabetes. Postulated mechanisms of this observation include prothrombotic effects. The aim of this study was to evaluate the effect of elevated glucose levels on blood clotting in acute coronary syndrome patients.RESEARCH DESIGN AND METHODS -We studied 60 acute coronary syndrome patients within the first 12 h after pain onset, including 20 subjects with type 2 diabetes, 20 subjects with no diagnosed diabetes but with glucose levels Ͼ7.0 mmol/l, and 20 subjects with glucose levels Ͻ7.0 mmol/l. We determined generation of thrombin-antithrombin complexes (TATs) and soluble CD40 ligand (sCD40L), a platelet activation marker, at the site of microvascular injury, together with ex vivo plasma fibrin clot permeability and lysis time.RESULTS -The acute coronary syndrome patients with no prior diabetes but elevated glucose levels had increased maximum rates of formation and total production of TATs (by 42.9%, P Ͻ 0.0001, and by 25%, P Ͻ 0.0001, respectively) as well as sCD40L release (by 16.2%, P ϭ 0.0011, and by 16.3%, P Ͻ 0.0001, respectively) compared with those with normoglycemia, whereas diabetic patients had the highest values of TATs and sCD40L variables (P Ͻ 0.0001 for all comparisons). Patients with hyperglycemia, with no previously diagnosed diabetes, had longer clot lysis time (by ϳ18%, P Ͻ 0.0001) similar to that in diabetic subjects, but not lower clot permeability compared with that in normoglycemic subjects.CONCLUSIONS -Hyperglycemia in acute coronary syndrome is associated with enhanced local thrombin generation and platelet activation, as well as unfavorably altered clot features in patients with and without a previous history of diabetes.

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“…Considerable evidence implicates the proinflammatory CD40 molecule, TNF receptor superfamily member 5 (CD40) ligand (CD40L or CD154) in atherosclerosis [2][3][4], and some recent data identify CD40/CD40L as a potential contributor to inflammation associated with obesity and its metabolic complications. Soluble CD40L (sCD40L) levels are increased in obese [5,6] and type 2 diabetic [7][8][9] individuals, as well as in individuals with the metabolic (insulin resistance) syndrome [10]. Variations in sCD40L plasma levels are strongly linked to differences in waist to hip ratio and to insulin sensitivity [11], with levels increased by exposure to hyperglycaemia and hyperinsulinaemia [12].…”

Section: Introductionmentioning

confidence: 99%

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

et al. 2009

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Aims/hypothesis Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation. Methods CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture. Results CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal-vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell-cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes. Conclusions/interpretation Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.

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Enhanced soluble CD40L in patients with the metabolic syndrome: relationship with in vivo thrombin generation

Cited by 41 publications

References 39 publications

The Levels of Soluble CD40 Ligand and C-Reactive Protein in Normal Weight, Overweight and Obese People

The Levels of Soluble CD40 Ligand and C-Reactive Protein in Normal Weight, Overweight and Obese People

Hyperglycemia Is Associated With Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients With Acute Coronary Syndrome

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

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