Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control

Abstract

Aims/hypothesis: Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs). Methods: We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O 2 − generation in monocytes were analysed in vitro after stimulation with serum from patients or controls. Results: Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O 2 − generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA 1 c levels. Conclusions/interpretation: Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.

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

“…The close association between sCD40L and F 1+2 has already been described in other atherosclerotic settings such as hypercholesterolaemia and diabetes [24][25][26], leading to the hypothesis that CD40L overexpression may be a stimulus for clotting activation. This hypothesis is based on previous studies [27][28][29][30][31] demonstrating that in monocytes, endothelial cells and smooth muscle cells CD40L overexpresses tissue factor, a glycoprotein of the extrinsic clotting pathway that triggers the coagulation cascade activating factor VII and in turn converts factor X to Xa.…”

CD40 Mediates Retinal Inflammation and Neurovascular Degeneration

“…These overlapping features between diabetic and I/R-induced retinopathies raise the possibility that CD40 is a mediator also of diabetic retinopathy. Relevant to this possibility is the evidence that points to activation of the CD40-CD154 pathway in diabetic retinopathy, because CD154 expression is increased in patients with this disease (48,49).…”

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

“…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].…”