Tetrahydrobiopterin prevents endothelial dysfunction and restores adiponectin levels in rats.
Oxidative stress induces endothelial dysfunction and hypoadiponectinemia. We previously reported that supplementation with tetrahydrobiopterin (BH4), one of the most potent naturally occurring reducing agents and an essential cofactor of enzymatic NO synthase (NOS), ameliorates endothelial dysfunction and reverses hypoadiponectinemia as a result of oxidative stress in rats. To further confirm this hypothesis, we investigated the effects of treatment with BH4 on endothelium-dependent relaxation and adiponectin levels during oxidative stress in fructose-fed rats, which provide an animal model for the metabolic syndrome. Ingestion of a fructose diet for 8 weeks significantly impaired endothelium-dependent arterial relaxation in aortic strips and decreased plasma adiponectin levels, as well as adiponectin mRNA levels within adipose tissue. However, oral supplementation with BH4 (10 mg/kg day) over the final 4 weeks leads to a significant partial reversal of impaired endothelium-dependent arterial relaxation, as well as normalization of plasma adiponectin and fat adiponectin mRNA levels. Moreover, BH4 treatment of the fructose-fed rats significantly reduced the lipid peroxidation content of aorta, heart, liver, and kidney tissues, which were increased in fructose-fed rats. This effect of BH4 treatment may be due to its function as a cofactor for eNOS, as well as its anti-oxidative effects. Thus, BH4 might show promise for the treatment of oxidative stress-induced disorders, including the metabolic syndrome.
Wang
Xi
X
Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Hattori
Yoshiyuki
Y
Satoh
Hiroko
H
Iwata
Chigusa
C
Banba
Nobuyuki
N
Monden
Tsuyoshi
T
Uchida
Kohsuke
K
Kamikawa
Yuichiro
Y
Kasai
Kikuo
K
D052242:Adiponectin / Q000097:blood / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D005632:Fructose; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood; D014664:Vasodilation / Q000187:drug effects
D052242:Adiponectin; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D014280:Triglycerides; D001708:Biopterins; D005632:Fructose; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C003402:sapropterin