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

574 Citations (Scopus)

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

Fingerprint

Peroxynitrous Acid
Apolipoproteins E
Endothelium
Nitric Oxide
Vasodilation
Nitric Oxide Synthase
Superoxides
Blood Vessels
Aorta
Uric Acid
Luminol
Luminescence
Liposomes
Hydrogen Peroxide
Superoxide Dismutase
sapropterin
Reactive Oxygen Species
Atherosclerosis
Endothelial Cells
Therapeutics

Keywords

  • Endothelium
  • Genes
  • Vessels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Laursen, J. B., Somers, M., Kurz, S., McCann, L., Warnholtz, A., Freeman, B. A., ... 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

Endothelial regulation of vasomotion in ApoE-deficient mice : Implications for interactions between peroxynitrite and tetrahydrobiopterin. / Laursen, Jørn Bech; Somers, Mark; Kurz, Sabine; McCann, Louise; Warnholtz, Ascan; Freeman, Bruce A.; Tarpey, Margaret; Fukai, Tohru; Harrison, David G.

In: Circulation, Vol. 103, No. 9, 06.03.2001, p. 1282-1288.

Research output: Contribution to journalArticle

Laursen, JB, Somers, M, Kurz, S, McCann, L, Warnholtz, A, Freeman, BA, Tarpey, M, Fukai, T & Harrison, DG 2001, 'Endothelial regulation of vasomotion in ApoE-deficient mice: Implications for interactions between peroxynitrite and tetrahydrobiopterin', Circulation, vol. 103, no. 9, pp. 1282-1288. https://doi.org/10.1161/01.CIR.103.9.1282
Laursen, Jørn Bech ; Somers, Mark ; Kurz, Sabine ; McCann, Louise ; Warnholtz, Ascan ; Freeman, Bruce A. ; Tarpey, Margaret ; Fukai, Tohru ; Harrison, David G. / Endothelial regulation of vasomotion in ApoE-deficient mice : Implications for interactions between peroxynitrite and tetrahydrobiopterin. In: Circulation. 2001 ; Vol. 103, No. 9. pp. 1282-1288.
@article{e64be9e10846414e8300d55dd5c9049d,
title = "Endothelial regulation of vasomotion in ApoE-deficient mice: Implications for interactions between peroxynitrite and tetrahydrobiopterin",
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.",
keywords = "Endothelium, Genes, Vessels",
author = "Laursen, {J{\o}rn Bech} and Mark Somers and Sabine Kurz and Louise McCann and Ascan Warnholtz and Freeman, {Bruce A.} and Margaret Tarpey and Tohru Fukai and Harrison, {David G.}",
year = "2001",
month = "3",
day = "6",
doi = "10.1161/01.CIR.103.9.1282",
language = "English (US)",
volume = "103",
pages = "1282--1288",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

TY - JOUR

T1 - Endothelial regulation of vasomotion in ApoE-deficient mice

T2 - Implications for interactions between peroxynitrite and tetrahydrobiopterin

AU - Laursen, Jørn Bech

AU - Somers, Mark

AU - Kurz, Sabine

AU - McCann, Louise

AU - Warnholtz, Ascan

AU - Freeman, Bruce A.

AU - Tarpey, Margaret

AU - Fukai, Tohru

AU - Harrison, David G.

PY - 2001/3/6

Y1 - 2001/3/6

N2 - 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.

AB - 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.

KW - Endothelium

KW - Genes

KW - Vessels

UR - http://www.scopus.com/inward/record.url?scp=0035814951&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035814951&partnerID=8YFLogxK

U2 - 10.1161/01.CIR.103.9.1282

DO - 10.1161/01.CIR.103.9.1282

M3 - Article

VL - 103

SP - 1282

EP - 1288

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 9

ER -