Objectives Reduced availability of tetrahydrobiopterin (BH4), an essential cofactor of NO synthase (NOS), decreases NO production and increases ROS. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH4 improves endothelial dysfunction, the effect of chronic BH4 in humans is unknown. We investigated the effect of chronic BH4 supplementation on endothelial function and oxidative stress in hypercholesterolemia.
Design Randomized double-blind placebo controlled.
Setting University Hospital
Patients 22 hypercholesterolemic patients (LDL>4.5mmol/L) were randomized to 4-weeks of oral BH4 (400 mg bid) or placebo. Age-matched healthy volunteers served as controls.
Main outcome measures Endothelium-dependent and iVindependent vasodilation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH4 effect, NO release and superoxide anion (O2-) production were measured in human aortic endothelial cells exposed to native LDL (100 mg cholesterol/dL).
Results BH4 plasma levels were significantly increased by oral supplementation. NO-mediated vasodilation to acetylcholine was reduced in patients compared with controls and restored by BH4. No effect of BH4 on endothelium-independent vasodilation was observed. Furthermore, 8-F2fnisoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH4. In LDL-treated endothelial cells, BH4 levels and NO release were reduced and O2- production increased compared to control cells. Exogenous BH4 normalized NO and O2-production.
Conclusions In hypercholesterolemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH4. Thus, BH4 availability is essential for maintaining NO synthesis and low O2- production by eNOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.
- free radicals