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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1655.)
© 2002 American Heart Association, Inc.

Atherosclerosis

Altered Tetrahydrobiopterin Metabolism in Atherosclerosis

Implications for Use of Oxidized Tetrahydrobiopterin Analogues and Thiol Antioxidants

Jeannette Vásquez-Vivar; Damon Duquaine; Jennifer Whitsett; B. Kalyanaraman; Sanjay Rajagopalan

From the Biophysics Research Institute (J.V.-V., B.K.) and Free Radical Research Center (J.V.-V., J.W., B.K.), Medical College of Wisconsin, Milwaukee, and the Department of Internal Medicine (D.D., S.R.), University of Michigan, Ann Arbor.

Correspondence to Sanjay Rajagopalan, Department of Internal Medicine. University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0273. E-mail srajagop{at}umich.edu

Abstract

Objective— Tetrahydrobiopterin (BH₄) 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 BH₄ 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 BH₄ 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 BH₄ levels, whereas NAC in conjunction with sepiapterin raised BH₄ 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 BH₄. Antioxidant thiols do not correct this impairment. These studies have implications for the use of sepiapterin in the correction of vasomotor tone in atherosclerosis.

Key Words: sepiapterin • N-acetylcysteine • endothelium • hypercholesterolemia • nitric oxide • tetrahydrobiopterin

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