Endothelial regulation of vasomotion in ApoE-deficient mice: Implications for interactions between peroxynitrite and tetrahydrobiopterin

Jørn Bech Laursen, Mark Somers, Sabine Kurz, Louise McCann, Ascan Warnholtz, Bruce A. Freeman, Margaret Tarpey, Tohru Fukai, David G. Harrison

Research output: Contribution to journalArticle

587 Scopus citations

Abstract

Background - Altered endothelial cell nitric oxide (NO.) production in atherosclerosis may be due to a reduction of intracellular tetrahydrobiopterin, which is a critical cofactor for NO synthase (NOS). In addition, previous literature suggests that inactivation of NO. by increased vascular production superoxide (O2.-) also reduces NO. bioactivity in several disease states. We sought to determine whether these 2 seemingly disparate mechanisms were related. Methods and Results - Endothelium-dependent vasodilation was abnormal in aortas of apoE-deficient (apoE-/-) mice, whereas vascular superoxide production (assessed by 5 μmol/L lucigenin) was markedly increased. Treatment with either liposome-entrapped superoxide dismutase or sepiapterin, a precursor to tetrahydrobiopterin, improved endothelium-dependent vasodilation in aortas from apoE-/- mice. Hydrogen peroxide had no effect on the decay of tetrahydrobiopterin, as monitored spectrophotometrically. In contrast, superoxide modestly and peroxynitrite strikingly increased the decay of tetrahydrobiopterin over 500 seconds. Luminol chemiluminescence, inhibitable by the peroxynitrite scavengers ebselen and uric acid, was markedly increased in apoE-/- aortic rings. In vessels from apoE-/- mice, uric acid improved endothelium-dependent relaxation while having no effect in vessels from control mice. Treatment of normal aortas with exogenous peroxynitrite dramatically increased vascular O2.- production, seemingly from eNOS, because this effect was absent in vessels lacking endothelium, was blocked by NOS inhibition, and did not occur in vessels from mice lacking eNOS. Conclusions - Reactive oxygen species may alter endothelium-dependent vascular relaxation not only by the interaction of O2.- with NO. but also through interactions between peroxynitrite and tetrahydrobiopterin. Peroxynitrite oxidation of tetrahydrobiopterin may represent a pathogenic cause of "uncoupling" of NO synthase.

Original languageEnglish (US)
Pages (from-to)1282-1288
Number of pages7
JournalCirculation
Volume103
Issue number9
DOIs
StatePublished - Mar 6 2001
Externally publishedYes

Keywords

  • Endothelium
  • Genes
  • Vessels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Laursen, J. B., Somers, M., Kurz, S., McCann, L., Warnholtz, A., Freeman, B. A., Tarpey, M., Fukai, T., & Harrison, D. G. (2001). Endothelial regulation of vasomotion in ApoE-deficient mice: Implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation, 103(9), 1282-1288. https://doi.org/10.1161/01.CIR.103.9.1282