19207718

pubmed:Citation

8

1. 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 (BH4) 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 BH4 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 BH4 and GTP cyclohydrolase I deficiency, resulting in endothelial dysfunction in Ins2(Akita) Type 1 diabetic mice fed a high-cholesterol diet.

eng

IM

MEDLINE

1440-1681

Electronic

NLM

764-9

pubmed-meshheading:19207718-Acetophenones, pubmed-meshheading:19207718-Animals, pubmed-meshheading:19207718-Biopterin, pubmed-meshheading:19207718-Cholesterol, Dietary, pubmed-meshheading:19207718-Diabetes Mellitus, Experimental, pubmed-meshheading:19207718-Diabetes Mellitus, Type 1, pubmed-meshheading:19207718-Endothelium, Vascular, pubmed-meshheading:19207718-Enzyme Inhibitors, pubmed-meshheading:19207718-Genes, Dominant, pubmed-meshheading:19207718-Insulin, pubmed-meshheading:19207718-Lipid Peroxides, pubmed-meshheading:19207718-Male, pubmed-meshheading:19207718-Mice, pubmed-meshheading:19207718-Mice, Inbred C57BL, pubmed-meshheading:19207718-Mice, Mutant Strains, pubmed-meshheading:19207718-Mutation, pubmed-meshheading:19207718-NADPH Oxidase, pubmed-meshheading:19207718-Oxidative Stress, pubmed-meshheading:19207718-Protein Precursors, pubmed-meshheading:19207718-Superoxides, pubmed-meshheading:19207718-Vasodilation

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.

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural