title: Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus.
abstract: 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.
authors.affiliation: Center of Excellence on Aging and Department of Medicine, University of Chieti G. D'Annunzio Schools of Medicine and Pharmacy, Chieti, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Santilli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Davì
authors.forename: Agostino
authors.initials: A
authors.lastname: Consoli
authors.forename: Francesco
authors.initials: F
authors.lastname: Cipollone
authors.forename: Andrea
authors.initials: A
authors.lastname: Mezzetti
authors.forename: Angela
authors.initials: A
authors.lastname: Falco
authors.forename: Tea
authors.initials: T
authors.lastname: Taraborelli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Devangelio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciabattoni
authors.forename: Stefania
authors.initials: S
authors.lastname: Basili
authors.forename: Carlo
authors.initials: C
authors.lastname: Patrono
mesh_terms: 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
chemical_list: 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