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

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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. 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. 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.