The Bilirubin-Increasing Drug Atazanavir Improves Endothelial Function in Patients With Type 2 Diabetes Mellitus

被引:111
作者
Dekker, Douwe [2 ]
Dorresteijn, Mirrin J. [2 ]
Pijnenburg, Margot
Heemskerk, Suzanne [3 ]
Rasing-Hoogveld, Anja
Burger, David M. [4 ]
Wagener, Frank A. D. T. G. [1 ,5 ]
Smits, Paul [2 ]
机构
[1] Radboud Univ Nijmegen, Med Ctr, Nijimegen Ctr Mol Life Sci, Dept Pharmacol & Toxicol, NL-6500 HB Nijmegen, Netherlands
[2] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands
[3] Radboud Univ Nijmegen, Med Ctr, Dept Intens Care Med, NL-6500 HB Nijmegen, Netherlands
[4] Radboud Univ Nijmegen, Med Ctr, Dept Pharm, NL-6500 HB Nijmegen, Netherlands
[5] Radboud Univ Nijmegen, Med Ctr, Dept Orthodont & Oral Biol, NL-6500 HB Nijmegen, Netherlands
关键词
antioxidants; atherosclerosis; endothelial function; reactive oxygen species; bilirubin; type 2 diabetes mellitus; LOW-DENSITY-LIPOPROTEIN; ORAL VITAMIN-C; DEPENDENT VASODILATION; OXIDATIVE STRESS; VASCULAR-DISEASE; GILBERT-SYNDROME; SERUM BILIRUBIN; HEME OXYGENASE; HIV-INFECTION; DYSFUNCTION;
D O I
10.1161/ATVBAHA.110.211789
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mu mol/L (0.4 mg/dL) to 64 mu mol/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. Conclusion-Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM. (Arterioscler Thromb Vasc Biol. 2011;31:458-463.)
引用
收藏
页码:458 / 463
页数:6
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