Faculty Collaboration Database

Altered tetrahydrobiopterin metabolism in atherosclerosis: implications for use of oxidized tetrahydrobiopterin analogues and thiol antioxidants. Arterioscler Thromb Vasc Biol 2002 Oct 01;22(10):1655-61

Date

10/16/2002

Pubmed ID

12377745

DOI

10.1161/01.atv.0000029122.79665.d9

Scopus ID

2-s2.0-0036790604 (requires institutional sign-in at Scopus site)   108 Citations

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 approximately 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.

Author List

Vásquez-Vivar J, Duquaine D, Whitsett J, Kalyanaraman B, Rajagopalan S

Authors

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin
Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetylcholine
Acetylcysteine
Animals
Antioxidants
Aorta, Thoracic
Arteriosclerosis
Calcimycin
Cholesterol
Diet
Endothelium, Vascular
Free Radical Scavengers
Hyperlipidemias
Ionophores
Male
Muscle, Smooth, Vascular
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type III
Oxidation-Reduction
Oxygen
Pteridines
Pterins
Rabbits
Sulfhydryl Compounds
Vasodilator Agents