TNF-α induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-γ agonist pioglitazone

Aims: Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-α, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-γ 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-α 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-α (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-α infusion (P=0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-α-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-α, interleukin-6, soluble TNF-α-receptors, or CD40L were observed. Conclusion: Pioglitazone treatment can convey direct protection against cytokine (TNF-α)-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.