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
C2 - 11238274
AN - SCOPUS:0035814951
SN - 0009-7322
VL - 103
SP - 1282
EP - 1288
JO - Circulation
JF - Circulation
IS - 9
ER -