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CLINICAL RESEARCH: DIABETES AND CARDIOVASCULAR DISEASE

Thromboxane-Dependent CD40 Ligand Release in Type 2 Diabetes Mellitus

Francesca Santilli, MD^_*, Giovanni Davì, MD^_*,_*, Agostino Consoli, MD^_*, Francesco Cipollone, MD^_*, Andrea Mezzetti, MD^_*, Angela Falco, MD^_*, Tea Taraborelli, PhD^_*, Eleonora Devangelio, MD^_*, Giovanni Ciabattoni, MD^_*, Stefania Basili, MD and Carlo Patrono, MD

^_* Center of Excellence on Aging and Departments of Medicine and Drug Sciences, University of Chieti G. D’Annunzio Schools of Medicine and Pharmacy, Chieti, Italy
Department of Medical Therapy, University of Rome La Sapienza, Rome, Italy.
Department of Pharmacology, University of Rome La Sapienza, Rome, Italy.

Manuscript received January 24, 2005; revised manuscript received March 3, 2005, accepted March 29, 2005.

^_* Reprint requests and correspondence: Dr. Giovanni Davì, Center of Excellence on Aging, University of Chieti, Via Colle dell’Ara, 66013 Chieti, Italy. (Email: gdavi{at}unich.it).

OBJECTIVES: 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)F₂ 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-PGF₂, 11-dehydro-TXB₂, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB₂ and 8-iso-PGF₂ 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-PGF₂, and 11-dehydro-TXB₂.

CONCLUSIONS: This study provides several lines of evidence for the dependence of sCD40L release on TXA₂-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.

Abbreviations and Acronyms   CRP = C-reactive protein   11-dehydro-TXB2 = 11-dehydro-thromboxane B2   HbA1c = hemoglobin A1c   IQR = interquartile range   8-iso-PGF2 = 8-iso-prostaglandin F2-alpha   LDL-C = low-density lipoprotein cholesterol   sCD40L = soluble CD40 ligand   T2DM = type 2 diabetes mellitus   TC = total cholesterol

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