Subject:
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IGMD 5: Health aging / healthy living N4i 1: Pathogenesis and modulation of inflammation N4i 1: Pathogenesis and modulation of inflammation IGMD 9: Renal disorder N4i 2: Invasive mycoses and compromised host N4i 3: Poverty-related infectious diseases NCEBP 13: Infectious diseases and international health NCEBP 14: Cardiovascular diseases NCMLS 3: Tissue engineering and pathology NCMLS 5: Membrane transport and intracellular motility N4i 1: Pathogenesis and modulation of inflammation |
Organization:
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Pharmacology-Toxicology Intensive Care Clinical Pharmacy Dentistry Internal Medicine |
Journal title:
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Arteriosclerosis, Thrombosis, and Vascular Biology
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Abstract:
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OBJECTIVE: In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM. METHODS AND RESULTS: In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 mumol/L (0.4 mg/dL) to 64 mumol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (P<0.001) and endothelium-dependent vasodilation (P=0.036) and a decrease in plasma von Willebrand factor (P=0.052) were observed. CONCLUSIONS: Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.
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