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Cardiovascular Research Advance Access first published online on February 15, 2008
This version [Accepted Manuscript] published online on February 22, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn040
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

TUMOR NECROSIS FACTOR {alpha} UP-REGULATES PLATELET CD40L IN PATIENTS WITH HEART FAILURE

Pasquale Pignatelli, MD*, Roberto Cangemi, MD*, Andrea Celestini, MD*, Roberto Carnevale, PhD*, Licia Polimeni, MD*, Alessandra Martini, MD*, Domenico Ferro, MD*, Lorenzo Loffredo, MD* and Francesco Violi, MD*,

* IV Divisione di Clinica Medica Department of Experimental Medicine and Pathology University of Rome "La Sapienza", Italy

Address for correspondence: Francesco Violi Department of Experimental Medicine and Pathology University of Rome "La Sapienza", Italy Policlinico Umberto I, 00185, Rome, Italy Tel +39 0644 61933 Fax +39 0649 970893 email francesco.violi{at}uniroma1.it

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 {alpha} (TNF{alpha}) and CD40L in heart failure.

Methods: In patients with HF (n= 85) and healthy subjects (HS, n= 43), plasma levels of soluble CD40L (sCD40L), TNF{alpha}, soluble receptors of TNF{alpha} such as soluble TNF receptor 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 TNF{alpha}.

Results: Compared to HS, HF patients had higher plasma values of sCD40L, TNF{alpha}, sTNFR1 and sTNFR2 and higher platelet expression of TNFR1 and TNFR2 with a progressive increase from NYHA I to NYHA IV classification. Soluble CD40L significantly correlated with TNF{alpha}, sTNFR1 and sTNFR2; plasma levels of TNF{alpha} significantly correlated with sCD40L. Incubation of platelets from HF patients with a TNF{alpha} receptor inhibitor significantly decreased platelet CD40L expression. The in vitro study demonstrated that TNF{alpha} 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.

Conclusions: The study shows that in HF patients, platelet CD40L is up-regulated by TNF{alpha} via a cyclooxygenase-1-independent, arachidonic acid-mediated oxidative stress mechanism.

Time for primary review: 25 days

This is a new version as the authors' first and last names were transposed in the first version.


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