Altered Tetrahydrobiopterin Metabolism in Atherosclerosis

Abstract

Objective— Tetrahydrobiopterin (BH ₄ ) is of fundamental importance for the normal function of endothelial NO synthase. The purpose of this study was to investigate the effects of hyperlipidemia on vascular BH ₄ levels and the effect of supplementation with sepiapterin in the presence and absence of N -acetylcysteine (NAC). Methods and Results— New Zealand White rabbits were fed normal chow (normocholesterolemic [NC] group) or hyperlipidemic chow (hyperlipidemic [HL] group) for 8 to 10 weeks. Mean cholesterol levels were 1465±333 and 53±17 mg/dL in the HL and NC group, respectively. Markedly diminished BH ₄ levels were found in the HL group compared with the NC group, but these levels could be restored after 6 hours of incubation with sepiapterin. Peak relaxations to acetylcholine and A23187 were impaired in the HL group. Supplementation with sepiapterin resulted in a further diminution of relaxation in the HL but not NC group. Incubation with NAC for 6 hours failed to raise BH ₄ levels, whereas NAC in conjunction with sepiapterin raised BH ₄ levels ≈221-fold. However, this increase did not improve relaxations to A23187 and acetylcholine. Conclusions— Prolonged exposure to sepiapterin impairs vasorelaxation in hyperlipidemia despite repletion of endogenous BH ₄ . Antioxidant thiols do not correct this impairment. These studies have implications for the use of sepiapterin in the correction of vasomotor tone in atherosclerosis.