Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control.
OBJECTIVE
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 O2- 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 O2- 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 HbA1c levels.


CONCLUSIONS
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.
Cipollone
F
F
Atherosclerosis Prevention Center, G. d'Annunzio University of Chieti, Chieti, Italy. fcipollone@inich.it
Chiarelli
F
F
Davì
G
G
Ferri
C
C
Desideri
G
G
Fazia
M
M
Iezzi
A
A
Santilli
F
F
Pini
B
B
Cuccurullo
C
C
Tumini
S
S
Del Ponte
A
A
Santucci
A
A
Cuccurullo
F
F
Mezzetti
A
A
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism*; D023201:CD40 Ligand / Q000097:blood*; D018932:Chemokine CCL2 / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D019040:E-Selectin / Q000097:blood; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology*; D005215:Fasting; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D001786:Blood Glucose; D018932:Chemokine CCL2; D019040:E-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand