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.
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.
Yang
Xiang-Qun
XQ
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA.
Chen
Alex F
AF
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000009:adverse effects*; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D007328:Insulin / Q000235:genetics*; D008054:Lipid Peroxides / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics*; D013481:Superoxides / Q000097:blood; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000098:Acetophenones; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D007328:Insulin; D008054:Lipid Peroxides; D011498:Protein Precursors; D013481:Superoxides; D001708:Biopterins; C013737:preproinsulin; C056165:acetovanillone; D019255:NADPH Oxidases; C003402:sapropterin