Tumour necrosis factor α upregulates platelet CD40L in patients with heart failure

Abstract

Aims: Patients with heart failure (HF) have elevated values of the pro-inflammatory protein CD40L but the underlying mechanism is unclear. This study was performed to evaluate the interplay between tumour necrosis factor α (TNFα) and CD40L in HF. Methods and results: In patients with HF (n = 86) and healthy subjects (HS, n = 43), plasma levels of soluble CD40L (sCD40L), TNFα, soluble receptors of TNFα such as soluble TNF receptors I and II (sTNFR1 and sTNFR2), and 8OH-dG, a marker of oxidative stress, were determined. Also, an in vitro study was performed by determining platelet CD40L regulation upon platelet stimulation with TNFα. Compared with HS, HF patients had higher plasma values of sCD40L, TNFα, sTNFR1 and sTNFR2, and higher platelet expression of TNFR1 and TNFR2 with a progressive increase from NYHA I to NYHA IV classification. sCD40L significantly correlated with TNFα, sTNFR1, and sTNFR2; plasma levels of TNFα significantly correlated with sCD40L. Incubation of platelets from HF patients with a TNFα receptor inhibitor significantly decreased platelet CD40L expression. The in vitro study demonstrated that TNFα significantly increased CD40L expression, an effect weakly influenced by aspirin but significantly reduced by AACOCF3, an inhibitor of PLA2, apocynin, an inhibitor of NADPH oxidase, or staurosporine, an inhibitor of PKC. Conclusion: The study shows that in HF patients, platelet CD40L is upregulated by TNFα via a cyclooxygenase-1-independent, arachidonic acid-mediated oxidative stress mechanism. © The Author 2008.