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HIGH‐CHOLESTEROL DIET AUGMENTS ENDOTHELIAL DYSFUNCTION VIA ELEVATED OXIDATIVE STRESS AND REDUCED TETRAHYDROBIOPTERIN IN INS2 AKITA MICE, AN AUTOSOMAL DOMINANT MUTANT TYPE 1 DIABETIC MODEL
Author(s) -
Yang XiangQun,
Chen Alex F
Publication year - 2009
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2009.05145.x
Subject(s) - apocynin , medicine , endocrinology , nadph oxidase , tetrahydrobiopterin , endothelial dysfunction , oxidative stress , endothelium , lipid peroxidation , gtp cyclohydrolase i , superoxide , streptozotocin , nitric oxide , high cholesterol , chemistry , cholesterol , nitric oxide synthase , biology , diabetes mellitus , biochemistry , enzyme
SUMMARY1 Oxidative stress contributes to endothelial dysfunction and atherogenesis in diabetes. The present study tested the hypothesis that a high‐cholesterol diet accelerates endothelial dysfunction in Ins2 Akita mice, a Type 1 diabetic model with a spontaneous autosomal preproinsulin gene ( Ins2 gene) mutation, through further increase of superoxide production. 2 The Ins2 Akita diabetic mice were fed a high‐cholesterol diet (1.25% cholesterol) for 4 months. Some Ins2 Akita mice were also treated for 4 months with the selective NADPH oxidase inhibitor apocynin (4 mg/kg per day in drinking water). Oxidative stress markers, tetrahydrobiopterin (BH 4 ) levels, GTP cyclohydrolase I activity and endothelial function were determined in serum or arteries afterwards. 3 Serum lipid peroxidation and arterial superoxide levels were increased, whereas arterial BH 4 levels and GTP cyclohydrolase I activity were decreased, in Ins2 Akita mice on a high‐cholesterol diet, resulting in impaired endothelium‐dependent nitric oxide‐mediated relaxation in response to acetylcholine. 4 In vivo treatment with apocynin not only blunted serum lipid peroxidation and arterial superoxide levels, but also increased BH 4 levels and GTP cyclohydrolase I activity, resulting in improved endothelium‐dependent relaxation. 5 These results suggest that NADPH oxidase may play a potential role in oxidative stress‐induced arterial BH 4 and GTP cyclohydrolase I deficiency, resulting in endothelial dysfunction in Ins2 Akita Type 1 diabetic mice fed a high‐cholesterol diet.