Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus.
OBJECTIVE
The goals of this study were to characterize the platelet contribution to soluble CD40 ligand (sCD40L), to correlate its formation with the extent of oxidative stress and platelet activation, and to investigate the effects of improved metabolic control and low-dose aspirin on these processes.


BACKGROUND
Inflammation, oxidative stress, and platelet activation are involved in the pathogenesis of type 2 diabetes (T2DM) and its complications. The CD40-CD40L interactions result in inflammatory and pro-thrombotic responses.


METHODS
Urinary 8-iso-prostaglandin (PG)F2alpha and 11-dehydro-thromboxane (TX)B2, in vivo markers of oxidative stress and platelet activation, respectively, plasma CD40L, and C-reactive protein (CRP) were measured in 114 T2DM patients and 114 control patients. A randomized, parallel group, 17-day study of aspirin (30, 100, or 325 mg/day) was performed in 18 T2DM patients. A similar study was performed in six healthy volunteers (aspirin, 100 mg/day). Twenty poorly controlled T2DM patients were studied before and after improved metabolic control.


RESULTS
Compared with control patients, diabetic patients showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB2 and 8-iso-PGF2alpha excretion rates predicted sCD40L levels. Soluble CD40L linearly correlated with 11-dehydro-TXB2 (rho = 0.67, p < 0.0001), and both were reduced after one week of aspirin (p < 0.0026), with slow recovery over 10 days after aspirin withdrawal. Improved metabolic control was associated with a reduction in sCD40L, 8-iso-PGF2alpha, and 11-dehydro-TXB2.


CONCLUSIONS
This study provides several lines of evidence for the dependence of sCD40L release on TXA(2)-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.
Santilli
Francesca
F
Center of Excellence on Aging and Department of Medicine, University of Chieti G. D'Annunzio Schools of Medicine and Pharmacy, Chieti, Italy.
Davì
Giovanni
G
Consoli
Agostino
A
Cipollone
Francesco
F
Mezzetti
Andrea
A
Falco
Angela
A
Taraborelli
Tea
T
Devangelio
Eleonora
E
Ciabattoni
Giovanni
G
Basili
Stefania
S
Patrono
Carlo
C
D000368:Aged; D001241:Aspirin / Q000008:administration & dosage*; D023201:CD40 Ligand / Q000378:metabolism*; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology*; D015539:Platelet Activation / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011863:Radioimmunoassay; D013928:Thromboxane A2 / Q000502:physiology*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine
D010975:Platelet Aggregation Inhibitors; D023201:CD40 Ligand; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; D013928:Thromboxane A2; C049235:11-dehydro-thromboxane B2; D015237:Dinoprost; D001241:Aspirin