(Circulation. 2001;103:1282.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Endothelial Regulation of Vasomotion in ApoE-Deficient Mice
Implications for Interactions Between Peroxynitrite and Tetrahydrobiopterin
From the Department of Medicine, Emory University School of Medicine, and Veterans Administration Hospital, Atlanta, Ga (J.B.L., M.S., S.K., L.M., A.W., T.F., D.G.H.); the Department of Anesthesia, University of Alabama, Birmingham (B.A.F., M.T.); and Medical Department B, Division of Cardiology, Rigshospitalet, Denmark (J.B.L.).
Correspondence to David G. Harrison, Professor of Medicine, Emory University School of Medicine, Cardiology Department, 1639 Pierce Dr, WMB-319, Atlanta, GA 30322. E-mail dharr02{at}emory.edu
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Abstract |
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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.
Key Words: endothelium • genes • vessels
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Introduction |
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There has been interest in mechanisms underlying abnormal endothelium-dependent vascular relaxation in hypercholesterolemia and atherosclerosis. Superoxide (O2·-) production is increased in atherosclerotic vessels1 2 and reacts rapidly with nitric oxide (NO·) to form the peroxynitrite anion. Increased nitrotyrosine immunostaining has provided indirect evidence for this interaction in atherosclerotic vessels.3 Membrane-targeted forms of superoxide dismutase (SOD) or antioxidant vitamins can enhance endothelium-dependent vascular relaxation in diverse pathological conditions, such as hypercholesterolemia, diabetes, hypertension, and cigarette smoking.4
Recently, there has been interest in the possibility that tetrahydrobiopterin, a critical cofactor for NO synthase (NOS), may be deficient in various conditions associated with altered endothelial function. For example, treatment with tetrahydrobiopterin has been shown to augment endothelium-dependent vasodilation in humans with hypercholesterolemia.5 In studies of purified NOS, removal of tetrahydrobiopterin results in endothelial NOS (eNOS) becoming "uncoupled," such that electrons flowing from the reductase domain to the oxygenase domain are diverted to molecular oxygen rather than to L-arginine.6 7 In this uncoupled state, O2·- is produced rather than NO·. There is indirect evidence to suggest that this might also occur in intact endothelial cells8 and vessels.9
The present experiments were performed to examine mechanisms that might be responsible for tetrahydrobiopterin depletion in endothelial cells leading to eNOS uncoupling. Our findings suggest that reactive oxygen species produced in endothelial cells not only enhance degradation of NO· but also alter eNOS function by oxidation of tetrahydrobiopterin.
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Methods |
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Animals Studied
ApoE-deficient (apoE-/-) mice were obtained from Breslow and colleagues (Rockefeller University, New York, NY).10 Offspring from these animals of either sex, 6 to 18 months old, were studied. Mice lacking eNOS (eNOS-/- mice) were obtained from Jackson Laboratories (Bar Harbor, Maine). C57Blk/6 mice were used as controls.
Materials Used
Liposome-entrapped Cu/Zn-SOD was prepared as
described previously.11
Sepiapterin was obtained from B. Schrick or from RBI. Ebselen was
obtained from Cayman Biochemicals and dissolved in ethanol (final
concentration 0.2%). Peroxynitrite was synthesized as previously
described12 or purchased
from Alexis. Luminol was dissolved in DMSO (final concentration 0.1%).
All other agents were obtained from Sigma in the highest grade
available. All drugs were prepared from stock solutions and dissolved
in distilled water immediately before use, unless otherwise
stated.
Studies of Vascular Reactivity
Thoracic aortas were rapidly removed and cut into
ring segments 
3 mm long and studied as previously
described.13 In preliminary
studies, the optimum resting tension for both control and
apoE-/- mouse aortas (n=5 for each) for
tone development to 80 mmol/L KCl was found to be 1.15 g. Vessels
were gradually stretched to this resting tension over 1 hour. In
general, 3 to 4 ring segments were studied from each animal. Relaxation
responses were performed on 2 separate rings, and the responses were
averaged and used to represent an "n" of 1.
Western Analysis
Western blots were performed as previously
described14 with a
polyclonal anti-eNOS antibody (1:1000 dilution) obtained from
Transduction Laboratories, and a mouse anti-rabbit IgG secondary
antibody (1:1000 dilution) from BioRad.
Spectrophotometric Analysis of
Tetrahydrobiopterin After Exposure to Reactive Oxygen Species
Tetrahydrobiopterin (1 mmol/L stock) was dissolved in
a 200-mmol/L Tris-HCl buffer (pH 7.4) previously purged extensively
with argon gas. Tetrahydrobiopterin (0.1 mmol/L final concentration)
was maintained anaerobically at 5°C until used (<1 hour). In control
experiments in which the spontaneous oxidation of tetrahydrobiopterin
was examined, 100 µL of the tetrahydrobiopterin solution was added to
900 µL of deoxygenated Tris buffer in a 1-mL sample cuvette. Buffer
without tetrahydrobiopterin was used in the reference cuvette.
Absorbance of tetrahydrobiopterin at 297
nm15 was followed for 500
seconds at room temperature. Under these conditions, loss of absorbance
represents the tetrahydrobiopterin oxidation after solvation of
atmospheric oxygen into the sample and was considered a background
tetrahydrobiopterin oxidation. The effect of 1 mmol/L hydrogen peroxide
on tetrahydrobiopterin oxidation was examined with catalase (1000
U/mL), Cu/Zn-SOD (100 U/mL), and hydrogen peroxide (1 mmol/L) added to
the reference cuvette and hydrogen peroxide with SOD (100 U/mL) to the
sample cuvette. To examine the reaction of
O2·- with
tetrahydrobiopterin, KO2 was dissolved in 50
mmol/L NaOH (8 mmol/L stock) and diluted to a final concentration of
800 µmol/L in sample cuvettes containing catalase (1000 U/mL, to
scavenge H2O2 formed by
dismutation of
O2·-). Decayed
KO2 and catalase (1000 U/mL) were added to the
reference cuvette. Peroxynitrite was added for a final concentration of
250 µmol/L in sample cuvettes containing catalase (1000 U/mL) and SOD
(100 U/mL). Reference cuvettes for these experiments contained decayed
peroxynitrite, SOD, and catalase. Decayed KO2
and OONO- controls were made by adjusting
the pH of stock solutions to 7 at 5 minutes before addition to
tetrahydrobiopterin. Representative absorbance spectra were obtained
before and after 500 seconds of exposure to the various reaction
conditions.
Chemiluminescence Estimates of Reactive Oxygen
Species Produced by Vascular Segments
To estimate vascular
O2·- production,
we used lucigenin-enhanced chemiluminescence. Two 2.5-mm ring segments
of mouse aorta were placed in scintillation vials containing
Krebs-HEPES buffer with 5 µmol/L lucigenin. This concentration of
lucigenin has been shown to accurately reflect levels of ambient
O2·- and is not
subject to the redox cycling and artifactual production of superoxide
observed with higher concentrations of the
agent.16 17 In
other studies, luminol (100 µmol/L) chemiluminescence was examined by
similar methods. Light emission was detected with a scintillation
counter programmed to an out-of-coincidence mode. Mean
chemiluminescence yields observed during the period of 15 to 20 minutes
after addition of the vessel segments were used to estimate rates of
production of the respective reactive oxygen
species.
Statistical Analysis
Data are presented as mean±SEM. Peak relaxations and
EC50s were compared by ANOVA. When significance
was indicated, a Duncan’s multiple range post hoc test was used. The
oxidation of tetrahydrobiopterin by various reactive oxygen species was
compared by unpaired t tests
with a Bonferroni correction for multiple comparisons. Significance was
considered present when probability values were
<0.05.
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Results |
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Responses to Acetylcholine, the Calcium Ionophore A23187, and Nitroglycerin
For studies of vascular relaxations, vessels were preconstricted with 1.0 µmol/L phenylephrine. This resulted in 1.01±0.07 and 0.97±0.11 g tone in the control and apoE-/- mouse aortas, respectively. These values were similar between untreated vessels and vessels pretreated with liposome-entrapped SOD and uric acid. In control mice, acetylcholine and the calcium ionophore A23187 produced relaxations of 83±3% (n=20) and 89±2% (n=15), respectively. These responses were significantly reduced in the aortas of apoE-/- mice, 52±4% (n=10) and 52±10% (n=6) (Figure 1
).
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To determine whether
O2·- reduces
endothelium-dependent vascular relaxation in
apoE-/- mouse aortas, ring segments were
incubated in solutions of Krebs/HEPES buffer containing
liposome-entrapped SOD (500 U in 1:1 dilution) for 20 minutes and then
mounted in the organ chamber for study. Liposome-entrapped SOD had no
effect on endothelium-dependent responses of normal aortas
(Figure 1
). In contrast, in vessels from
apoE-/- mice, relaxations to
acetylcholine and A23187 were markedly enhanced by preincubation with
liposome-entrapped SOD
(Figure 1). Responses to nitroglycerin were shifted rightward
in vessels from apoE-/- mice.
Surprisingly, liposome-entrapped SOD reduced relaxations to
nitroglycerin in control mice, while having no effect on responses to
nitroglycerin in apoE-/- mice
(Figure 1).
Preincubation with the tetrahydrobiopterin precursor
sepiapterin (10 µmol/L) for 1 hour also improved peak
endothelium-dependent vascular relaxation to acetylcholine and A23187
in vessels from apoE-/- mice
(Figure 2). In normal vessels, sepiapterin slightly, but not
significantly, increased endothelium-dependent vascular relaxations to
A23187, while having no effect on responses to acetylcholine
(Figure 2).
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Expression of eNOS in Control C57Blk/6 and
apoE-/- Mouse Aortas
As shown in
Figure 1, liposome-entrapped SOD increased
endothelium-dependent vascular relaxations to levels exceeding that of
normal vessels, suggesting that eNOS protein might be increased in
apoE-/- mouse aortas. Indeed, levels of
eNOS protein, as assessed by Western analysis, were significantly
greater in apoE-/- than in C57Blk/6
aortic homogenates (n=3,
Figure 3).
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Superoxide Production by Control C57Blk/6 and
apoE-/- Mouse Aortas
The finding that liposome-entrapped SOD enhanced
endothelium-dependent vascular relaxation in aortas of
apoE-/- mice strongly suggested that
production of
O2·- may be
increased in these vessels. Estimates of
O2·- production
by use of lucigenin-enhanced chemiluminescence confirmed this. As shown
in
Figure 4, O2·- production
was markedly increased in apoE-/- mouse
aortas compared with controls. Removal of the endothelium dramatically
reduced O2·-
production from apoE-/- mouse aortas,
while having little effect in control vessels. Exposure of aortic
segments from apoE-/- mice to
sepiapterin (10 µmol/L) for 1 hour before the lucigenin assay reduced
O2·- production
in aortas of apoE-/- mice, while having
no effect in vessels from control C57Blk/6 mice
(Figure 4). NG-Nitro-L-arginine methyl ester (L-NAME) (1
mmol/L) dramatically increased
O2·- production
in control vessels, while having no effect in the
apoE-/- vessels. Taken together, these
data suggest that the endothelium produces large amounts of
O2·- in the
atherosclerotic aortas of apoE-/-
mice.
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Interaction of Tetrahydrobiopterin With
Reactive Oxygen Species
Because both liposome-entrapped SOD and sepiapterin
corrected endothelium-dependent vascular relaxations in atherosclerotic
vessels of the apoE-/- mice and these
vessels seemed to produce large quantities of reactive oxygen species,
we considered the hypothesis that either
O2·- or a
reactive oxygen species derived from
O2·- might
oxidize tetrahydrobiopterin. Tetrahydrobiopterin and dihydrobiopterin
could easily be differentiated by their respective absorbances at 282
and 297 nm
(Figure 5A, top). Simple exposure to air resulted in loss of
17% of tetrahydrobiopterin over the 500 seconds of observation.
Exposure of tetrahydrobiopterin to hydrogen peroxide did not alter this
rate of degradation
(Figure 5B). In contrast, exposure to superoxide, derived
from KO2, modestly increased degradation of
tetrahydrobiopterin (P=0.04).
Exposure to even lower concentrations of peroxynitrite resulted in a
marked decline of tetrahydrobiopterin such that only 40% remained
after 500 seconds (P=0.0004).
The spectra after exposure to peroxynitrite resembled that of
dihydrobiopterin
(Figure 5A). Addition of sodium borohydride (1 mmol/L)
restored the tetrahydrobiopterin absorbance after exposure to
peroxynitrite
(Figure 5B).
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Evidence for Increased Production of
Peroxynitrite in ApoE-/- Mouse
Aortas
Using luminol
chemiluminescence,18 we next
sought to determine whether apoE-/-
mouse vessels produced excessive quantities of peroxynitrite. Luminol
chemiluminescence was dramatically enhanced in
apoE-/- mouse aortas. Both ebselen, a
scavenger of both H2O2
and peroxynitrite,19 and
uric acid, a scavenger of
peroxynitrite,20 reduced
luminol chemiluminescence in control and
apoE-/- mouse aortas, although the
degree of inhibition in apoE-/- aortas
was much greater than in control C57Blk/6 mouse aortas
(Figure 6). These data indicate that atherosclerotic vessels
from apoE-/- mice produce much larger
quantities of peroxynitrite than do normal
vessels.
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Effect of Uric Acid on Endothelium-Dependent
Vascular Relaxations
The above experiments indicated that peroxynitrite
could readily oxidize tetrahydrobiopterin in vitro and that
peroxynitrite is made in large quantities in atherosclerotic vessels.
To determine whether peroxynitrite might impair endothelium-dependent
vascular relaxation in intact vessels, 12 additional mice were studied.
These included 6 C57Blk/6 and 6 apoE-/-
mice, 18 months old. Studies of vascular relaxation were performed as
described above in 4 rings from each animal. In these studies, half of
the ring segments were exposed to the peroxynitrite scavenger uric acid
(100 µmol/L)21 for 20
minutes before and during vasodilation studies. As shown in
Figure 7, uric acid significantly increased the sensitivity
of vessels from apoE-/- mice to both
acetylcholine and A23187, but not to nitroglycerin. In contrast, uric
acid had no effect on responses in aortas of C57B/6 mice
(Figure 7).
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Evidence That Peroxynitrite Can Increase
O2·- Production
From eNOS in Intact Vascular Segments
The data above suggest that in atherosclerotic aortas,
peroxynitrite is formed and may interfere with eNOS function by
oxidizing tetrahydrobiopterin. We therefore reasoned that exogenously
administered peroxynitrite might uncouple eNOS and thus increase
vascular O2·-
production in normal mouse aortas. Aortic segments of C57Blk/6 mice
were exposed to peroxynitrite (100 µmol/L). Thirty minutes later, the
vascular rings were washed 2 times in Krebs/HEPES buffer and then
examined for lucigenin-enhanced chemiluminescence. In vessels with
intact endothelium, treatment with peroxynitrite increased
lucigenin-enhanced chemiluminescence almost 3-fold (1124±189 versus
2965±377
counts· min-1 · mg-1
in control versus peroxynitrite-treated aortas, respectively,
Figure 8). Because peroxynitrite (which has a half-life of
only several seconds) was added >0.5 hour before the lucigenin
estimates of O2·-
production, these findings strongly suggest that peroxynitrite produces
a long-lasting effect on vascular
O2·- production.
In vessels in which the endothelium had been removed, peroxynitrite did
not increase, and in fact paradoxically decreased, lucigenin-enhanced
chemiluminescence. The NO synthase inhibitor L-NAME completely
prevented the increase in
O2·- production
caused by peroxynitrite, as did treatment of the vessels with
sepiapterin. Importantly, peroxynitrite had no effect on
O2·- production
in vessels from eNOS-/- mice
(Figure 8).
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Discussion |
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Isometric tension studies of isolated vascular rings showed that both O2·- scavenging and treatment with a tetrahydrobiopterin precursor improved endothelium-dependent vasodilation in apoE-/- mouse aortas. Although there may be completely independent explanations for these findings, studies of interactions between reactive oxygen species and tetrahydrobiopterin suggested a common mechanism. Peroxynitrite potently oxidized tetrahydrobiopterin to dihydrobiopterin. Of note, peroxynitrite was more potent than larger concentrations of O2·- or H2O2. The relative effectiveness of these various reactive species in oxidizing tetrahydrobiopterin is in keeping with their known redox properties. In the absence of reductants and metals that would catalyze the reduction of H2O2 to ·OH, H2O2 is relatively stable and is a mild oxidant (Eo'=+320).22 Likewise, although O2·- has both reducing and oxidizing capacity, in most instances, donation of electrons (reduction) from superoxide rather than oxidation is favored.23 Our findings are also compatible with a recent report showing that peroxynitrite may oxidize tetrahydrobiopterin.24
In keeping with the concept that peroxynitrite may alter endothelium-dependent vascular relaxation, we found that uric acid, a peroxynitrite scavenger, significantly enhanced responses to acetylcholine and the calcium ionophore. The effect of uric acid was not as great as that of liposome-entrapped SOD. This is compatible with the notion that scavenging of O2·- would improve endothelium-dependent vascular relaxation via 2 mechanisms, preventing direct reactions with NO· and secondarily preventing the formation of peroxynitrite and consequent oxidation of tetrahydrobiopterin. In contrast, treatment with uric acid would be expected to prevent the only latter of these. Importantly, the reduction potentials of uric acid and superoxide do not favor reactions between the two.25 Uric acid could react with other strong oxidants that might also oxidize tetrahydrobiopterin, including hydroxyl and hypochlorous acid.26 Our studies do not exclude a role for such oxidants, although these would not likely be eliminated by liposome-entrapped SOD.
In the present study, sepiapterin only partially decreased O2·- production in apoE-/- mice, suggesting that sources other than eNOS may produce O2·- in these vessels. Studies using L-NAME to inhibit O2·- production were difficult to interpret, because L-NAME dramatically increased O2·- production in normal vessels, while having no effect in the apoE-/- aortas. The fact that L-NAME can increase lucigenin-enhanced chemiluminescence production in normal vessels is in keeping with the concept that a portion of NO· produced in these vessels is tonically inactivated by O2·-. The fact that L-NAME had minimal effect in the atherosclerotic vessels indicates that sources other than NO synthase almost certainly contribute. One such source is the NADH/NADPH oxidase, which represents a major source of reactive oxygen species in vascular cells and in atherosclerotic vessels. Our data are compatible with the concept that the simultaneous production of both O2·- (regardless of the source) and NO·, leading to peroxynitrite formation and oxidation of tetrahydrobiopterin, could result in uncoupling of eNOS such that O2·- was formed rather than NO·.6 7 This would result in a self-propagating condition whereby peroxynitrite formation could promote production of O2·-. Indeed, this seemed to be the case in our studies of normal vessels exposed briefly to exogenous peroxynitrite. This led to a sustained production of O2·- that was almost certainly from eNOS, because it could be prevented by either L-NAME or sepiapterin and did not occur when aortic segments from eNOS-/- mice were exposed to peroxynitrite.
Recently, the heme domain of eNOS has been crystallized and the tetrahydrobiopterin-binding site characterized.27 This region contains paired cysteine residues that coordinate binding of a zinc sulfate, which in turn seems to be critical in maintaining the integrity of tetrahydrobiopterin binding. The authors proposed that ZnS4 release may be controlled by redox status of the cell. Thus, exposure of eNOS to a strong oxidant, such as peroxynitrite, may not only oxidize intracellular tetrahydrobiopterin but also affect tetrahydrobiopterin binding by eNOS. It is also possible that oxidation of cytosolic tetrahydrobiopterin could affect eNOS function by reducing pterin availability for the enzyme. Addition of tetrahydrobiopterin to endothelial cell homogenates is essential to demonstrate optimum activity of eNOS, suggesting that the pterin may be readily lost from the intact enzyme.
By Western analysis, eNOS expression was not reduced but rather was increased in the descending thoracic aortas of apoE-/- mice compared with control aortas. This is in accordance with the finding that liposome-entrapped SOD increased endothelium-dependent vascular relaxation to supernormal levels in these vessels. Recently, we have shown that H2O2, the product of O2·- dismutation, is also a potent stimulus for eNOS expression.28 Thus, H2O2 and other factors may increase eNOS expression in endothelial cells overlying atherosclerotic lesions.
Previous work has suggested that inflammatory cytokines, like those found in atherosclerotic lesions, can stimulate expression of cyclohydrolase-1 in a variety of cell types, including endothelial cells.29 This would lead to higher rather than lower levels of pterins in atherosclerotic vessels. Our studies do not refute this finding but suggest that when the production of reactive oxygen species is increased, excessive oxidation of the pterins may be produced by the induced cyclohydrolase.
Taken together, these findings provide a new mechanism whereby reactive oxygen species can affect endothelial production of NO. In addition to the well-recognized reaction between NO· and O2·-, it appears that the radical-radical termination product of the reaction between these 2 species, OONO-, can oxidize a critical cofactor for the NO synthase enzyme tetrahydrobiopterin, leading to uncoupling of the enzyme. In either case, endothelial control of vasomotion would be impaired and would be improved by scavenging of O2·-. It should be noted that tetrahydrobiopterin is also a cofactor for aromatic amino acid hydroxylases, such as phenylalanine hydroxylase, which catalyzes formation of L-tyrosine from L-phenylalanine. Thus, these results may have implications for other aspects of cellular metabolism in conditions in which OONO- is produced in excess. Finally, oxidation of tetrahydrobiopterin by peroxynitrite may result in uncoupling of eNOS in numerous conditions other than atherosclerosis in which this oxidant is formed.
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Acknowledgments |
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This study was supported by NIH grant RO-1-HL-39006, Vascular Biology Program project grants HL-48667 and HL-48676, and a VA Merit Grant.
Received July 31, 2000; revision received September 8, 2000; accepted September 14, 2000.
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F. M. Faraci and S. P. Didion Vascular Protection: Superoxide Dismutase Isoforms in the Vessel Wall Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1367 - 1373. [Abstract] [Full Text] [PDF]
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M. d. C. P. Franco, Z. B. Fortes, E. H. Akamine, E. M. Kawamoto, C. Scavone, L. R. G. de Britto, M. N. Muscara, S. A. Teixeira, R. C. A. Tostes, M. H. C. Carvalho, et al. Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats J. Physiol., July 1, 2004; 558(1): 239 - 248. [Abstract] [Full Text] [PDF]
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S. Kawashima and M. Yokoyama Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 998 - 1005. [Abstract] [Full Text] [PDF]
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U. Landmesser, B. Hornig, and H. Drexler Endothelial Function: A Critical Determinant in Atherosclerosis? Circulation, June 1, 2004; 109(21_suppl_1): II-27 - II-33. [Abstract] [Full Text] [PDF]
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J. M. Sasser, J. C. Sullivan, A. A. Elmarakby, B. E. Kemp, D. M. Pollock, and J. S. Pollock Reduced NOS3 Phosphorylation Mediates Reduced NO/cGMP Signaling in Mesenteric Arteries of Deoxycorticosterone Acetate-Salt Hypertensive Rats Hypertension, May 1, 2004; 43(5): 1080 - 1085. [Abstract] [Full Text] [PDF]
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O. Jung, J.G. Schreiber, H. Geiger, T. Pedrazzini, R. Busse, and R.P. Brandes gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension Circulation, April 13, 2004; 109(14): 1795 - 1801. [Abstract] [Full Text] [PDF]
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N. J. Alp and K. M. Channon Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 413 - 420. [Abstract] [Full Text]
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N. J. Alp, M. A. McAteer, J. Khoo, R. P. Choudhury, and K. M. Channon Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 445 - 450. [Abstract] [Full Text]
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S. O. Hynes, L. A. Smith, D. M. Richardson, I. Kovesdi, T. O'Brien, and Z. S. Katusic In vivo expression and function of recombinant GTPCH I in the rabbit carotid artery Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H570 - H574. [Abstract] [Full Text] [PDF]
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J. Zhu, T. Mori, T. Huang, and J. H. Lombard Effect of high-salt diet on NO release and superoxide production in rat aorta Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H575 - H583. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, J. F. Keaney Jr., and M. A. Creager Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2392 - H2398. [Abstract] [Full Text] [PDF]
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U. Hink, M. Oelze, P. Kolb, M. Bachschmid, M.-H. Zou, A. Daiber, H. Mollnau, M. August, S. Baldus, N. Tsilimingas, et al. Role for peroxynitrite in the inhibition of prostacyclin synthase in nitrate tolerance J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1826 - 1834. [Abstract] [Full Text] [PDF]
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T. Munzel, R. Feil, A. Mulsch, S. M. Lohmann, F. Hofmann, and U. Walter Physiology and Pathophysiology of Vascular Signaling Controlled by Cyclic Guanosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase Circulation, November 4, 2003; 108(18): 2172 - 2183. [Full Text] [PDF]
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K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part II: Animal and Human Studies Circulation, October 28, 2003; 108(17): 2034 - 2040. [Full Text] [PDF]
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T. Mori and A. W. Cowley Jr Angiotensin II-NAD(P)H Oxidase-Stimulated Superoxide Modifies Tubulovascular Nitric Oxide Cross-Talk in Renal Outer Medulla Hypertension, October 1, 2003; 42(4): 588 - 593. [Abstract] [Full Text] [PDF]
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M. A. Creager, T. F. Luscher, F. Cosentino, and J. A. Beckman Diabetes and Vascular Disease: Pathophysiology, Clinical Consequences, and Medical Therapy: Part I Circulation, September 23, 2003; 108(12): 1527 - 1532. [Full Text] [PDF]
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J.-S. Zheng, X.-Q. Yang, K. J. Lookingland, G. D. Fink, C. Hesslinger, G. Kapatos, I. Kovesdi, and A. F. Chen Gene Transfer of Human Guanosine 5'-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension Circulation, September 9, 2003; 108(10): 1238 - 1245. [Abstract] [Full Text] [PDF]
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X. Gu, A. B. El-Remessy, S. E. Brooks, M. Al-Shabrawey, N.-T. Tsai, and R. B. Caldwell Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite Am J Physiol Cell Physiol, September 1, 2003; 285(3): C546 - C554. [Abstract] [Full Text] [PDF]
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