Oral Administration of Tetrahydrobiopterin Prevents Endothelial Dysfunction and Vascular Oxidative Stress in the Aortas of Insulin-Resistant Rats

Abstract

Abstract —We have reported that a deficiency of tetrahydrobiopterin (BH 4 ), an active cofactor of endothelial NO synthase (eNOS), contributes to the endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O 2 − ) generation in the insulin-resistant state. To further confirm this hypothesis, we investigated the effects of dietary treatment with BH 4 on endothelium-dependent arterial relaxation and vascular oxidative stress in the aortas of insulin-resistant rats. Oral supplementation of BH 4 (10 mg · kg −1 · d −1 ) for 8 weeks significantly increased the BH 4 content in cardiovascular tissues of rats fed high levels of fructose (fructose-fed rats). Impairment of endothelium-dependent arterial relaxation in the aortic strips of the fructose-fed rats was reversed with BH 4 treatment. The BH 4 treatment was associated with a 2-fold increase in eNOS activity as well as a 70% reduction in endothelial O 2 − production compared with those in fructose-fed rats. The BH 4 treatment also partially improved the insulin sensitivity and blood pressure, as well as the serum triglyceride concentration, in the fructose-fed rats. Moreover, BH 4 treatment of the fructose-fed rats markedly reduced the lipid peroxide content of both aortic and cardiac tissues and inhibited the activation of 2 redox-sensitive transcription factors, nuclear factor-κB and activating protein-1, which were increased in fructose-fed rats. The BH 4 treatment of control rats did not have any significant effects on these parameters. These results indicate that BH 4 augmentation is essential for the restoration of eNOS function and the reduction of vascular oxidative stress in insulin-resistant rats.