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European Heart Journal Advance Access originally published online on June 8, 2006
European Heart Journal 2006 27(13):1605-1609; doi:10.1093/eurheartj/ehl079
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

TNF-{alpha} induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-{gamma} agonist pioglitazone

Fabrice M.A.C. Martens1, Ton J. Rabelink2, Jos op 't Roodt2, Eelco J.P. de Koning2 and Frank L.J. Visseren1,*

1 Department of Internal Medicine, Section of Vascular Medicine, University Medical Center Utrecht, F02.126, Heidelberglaan 100, PO Box 85500, 3508 GA Utrecht, The Netherlands
2 Department of Nephrology, Leiden University Medical Center, The Netherlands

Received 10 October 2005; revised 24 April 2006; accepted 19 May 2006; online publish-ahead-of-print 8 June 2006.

* Corresponding author. Tel: +31 30 2509111; fax: +31 30 2518328. E-mail address: F.L.J.Visseren{at}umcutrecht.nl

Aims Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-{alpha}, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-{gamma} agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF-{alpha} on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus.

Methods and results A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF-{alpha} (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF-{alpha} infusion (P=0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-{alpha}-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-{alpha}, interleukin-6, soluble TNF-{alpha}-receptors, or CD40L were observed.

Conclusion Pioglitazone treatment can convey direct protection against cytokine (TNF-{alpha})-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.

Key Words: Diabetes mellitus • Endothelial function • Inflammation • Pioglitazone • Tumour necrosis factor-{alpha}


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