© 2000 American Heart Association, Inc.
Brief Reviews |
Nitric Oxide Regulation of Free Radical– and Enzyme-Mediated Lipid and Lipoprotein Oxidation
From the Departments of Anesthesiology (A.B., B.A.F.), Biochemistry and Molecular Genetics (A.B., B.A.F.), and The Center for Free Radical Biology (A.B., B.A.F.), University of Alabama at Birmingham, and the Wales Heart Research Institute (V.B.O.), University of Wales College of Medicine, Heath Park, Cardiff, UK.
Correspondence to Bruce A. Freeman, MD, Department of Anesthesiology, 946 THT, 619 19th St South, University of Alabama at Birmingham, Birmingham, AL 35233. E-mail bruce.freeman{at}ccc.uab.edu
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Abstract |
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Abstract—The regulation of nonenzymatic and enzymatic lipid oxidation reactions by nitric oxide (·NO) is potent and pervasive and reveals novel non–cGMP-dependent reactivities for this free radical inflammatory and signal transduction mediator. ·NO and its metabolites stimulate and inhibit lipid peroxidation reactions, modulate enzymatically catalyzed lipid oxidation, complex with lipid-reactive metals, and alter proinflammatory gene expression. Through these mechanisms, ·NO can regulate nonenzymatic lipid oxidation and the production of inflammatory and vasoactive eicosanoids by prostaglandin endoperoxide synthase and lipoxygenase. The accumulation of macrophages and oxidized low density lipoprotein within the vascular wall can also be modulated by ·NO. A key determinant of the pro-oxidant versus oxidant-protective influences of ·NO is the underlying oxidative status of tissue. When ·NO is in excess of surrounding oxidants, lipid oxidation and monocyte margination into the vascular wall are attenuated, producing antiatherogenic effects. However, when endogenous tissue rates of oxidant production are accelerated or when tissue oxidant defenses become depleted, ·NO gives rise to secondary oxidizing species that can increase membrane and lipoprotein lipid oxidation as well as foam cell formation in the vasculature, thus promoting proatherogenic effects. In summary, ·NO is a multifaceted molecule capable of reacting via multiple pathways to modulate lipid oxidation reactions, thereby impacting on tissue inflammatory reactions.
Key Words: nitric oxide • peroxynitrite • nitrogen dioxide • lipid oxidation • atherosclerosis • macrophages
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Introduction |
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Nitric oxide (·NO, nitrogen monoxide) is recognized for maintaining vascular tone by stimulating cGMP synthesis. Independent of this activation of soluble guanylate cyclase (sGC), other mechanisms can underlie the multifaceted roles of ·NO as a mediator of vascular function and inflammatory responses. ·NO and its metabolites are capable of stimulating and inhibiting lipid oxidation, modulating enzymatically catalyzed lipid oxidation, complexing with lipid-reactive metals, and altering proinflammatory gene expression. Through these mechanisms, ·NO can potentially regulate lipid oxidation and eicosanoid synthesis, thereby impacting on the genesis and progression of inflammatory vascular diseases. The influence of ·NO is a function of the local cellular milieu of reactive oxygen species, which biological antioxidants are present, the relative concentrations of reactants and substrates, and the relative rate constants of possible reactions.
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·NO Biosynthesis and Physical-Chemical Properties |
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·NO, a free radical signal-transducing agent, is synthesized endogenously by nitric oxide synthase (NOS) isoenzymes that oxidizes L-arginine to L-citrulline and are present in a variety of cell types, including vascular endothelial cells, smooth muscle cells, platelets, neuronal cells, macrophages, and neutrophils.1 There are constitutive NOS (neuronal NOS [type I] and endothelial NOS ([type III]) isoforms as well as an inducible NOS (iNOS, type II). Unlike typical signaling molecules, ·NO is freely diffusible, reacts with a diverse array of intracellular targets, and manifests biological effects that are dependent on the local chemical environment.2 ·NO is a small lipophilic molecule with a biological half-life of several seconds; thus, it can easily diffuse into and across plasma membranes and lipoproteins. As a free radical, ·NO readily reacts with other radical species (eg, superoxide [O2·-], lipid alkoxyl [LO·], and peroxyl [LOO·] radicals) and the metal centers of metalloproteins. The most well-characterized metal-binding action of ·NO is its capacity to bind to the heme iron of sGC and stimulate the production of cGMP.3 This activates cGMP-dependent kinases and membrane ion channels, decreases intracellular calcium levels, and allows smooth muscle to relax.4 Thus, ·NO has been identified as an endothelium-derived relaxing factor and as a central modulator of blood pressure.5 Stimulation of sGC by ·NO also inhibits platelet aggregation and vessel wall adhesion of platelets.
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Oxidative Reactions of ·NO |
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There are also critical guanylate cyclase–independent reactions of ·NO. The major biological end products of ·NO metabolism are nitrite (NO2-) and nitrate (NO3-), both of which are excreted in the urine. During metabolism to NO2-/NO3-, ·NO can undergo a series of reactions that generate reactive nitrogen species having a variety of oxidative states (Table 1
). Aerobically,
·NO reacts with oxygen to form nitrogen dioxide
(·NO2; see Equation 1).
Because ·NO and oxygen can concentrate 2- to 8-fold in
membranes, the reaction between ·NO and oxygen can be
accelerated up to 300-fold in a hydrophobic environment, such as the
core of LDL or membranes, in contrast to an aqueous
environment.6
 | (1) |
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When ·NO2 reacts with
·NO or another molecule of
·NO2, the nitrosating species
dinitrogen trioxide (N2O3)
and dinitrogen tetroxide
(N2O4), respectively, can
be formed (Equations 2 and 3):
 | (2) |
 | (3) |
Within the vascular system, ·NO may be removed by
reacting with oxyhemoglobin to form methemoglobin and
NO3-, where
k=3.4x107
(mol/L)-1 · s-1,7
with recent reports questioning the rate and extent of this reaction in
the vasculature.8 9 ·NO reacts with
superoxide (O2·-) at a
diffusion-limited rate, 1.9x1010
(mol/L)-1 · s-1
(see Equation 410 ), to form peroxynitrite
(ONOO-). ONOO-
is a highly reactive species with a half-life of
1.0 second at 37°C and pH 7.411 that reacts with
proteins, lipids, carbohydrates, and DNA of subcellular organelles and
cell systems through oxidation and nitration mechanisms.12
ONOO- also readily reacts with carbon dioxide
(CO2) to form a highly reactive
nitrosoperoxocarbonate intermediate
(ONOOCO2-; see Equation 5). Whereas ONOOCO2-
will not diffuse as far as ONOO- because of its
short half-life (<1 ms), the net reactivity of
ONOO- is shifted from an oxidizing species to a
nitrating species on reaction with
CO2.13 14
 | (4) |
 | (5) |
An inflammatory cell–mediated mechanism for formation of other
nitrating ·NO-derived species is the reaction of
NO2- with hypochlorous acid
(HOCl) to form a nitryl chloride intermediate
(Cl-NO2; see Equation 616 ). Also,
myeloperoxidase, found in neutrophils and monocytes, oxidizes
NO2- and chloride to generate
additional ·NO2 and HOCl-derived
·NO metabolites.17
 | (6) |
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·NO-Derived Reactive Nitrogen Species Influence Lipid Oxidation Through Oxidant and Antioxidant Mechanisms |
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Reactive Nitrogen Species Directly Modulate Lipid Oxidation in a Concentration-Dependent Manner
·NO and its products can stimulate and inhibit lipid peroxidation. The effects of ·NO on lipid oxidation depend on relative concentrations of ·NO, reactive oxygen species, and antioxidants, with all interactions in turn influenced by the aqueous-lipid solubility and relative rates of reaction of the participating reactive species.18 19 The influence of ·NO on lipid oxidation depends on the relative concentrations of ·NO and O2·- and organic peroxyl radicals (ROO·) present in the immediate vicinity. First, when the concentration of ·NO increases, so does the rate of reaction between ·NO and oxygen to form the oxidant, ·NO2. Second, ·NO reacts with O2·- and ROO· at nearly diffusion-limited rates: k=1.9x1010 (mol/L)-1 · s-110 and k=1 to 3x109 (mol/L)-1 · s-120 for O2·- and ROO·, respectively. Thus, ·NO can be pro-oxidative because of the formation of ONOO-. For example, when liposomes exposed to xanthine oxidase (1 µmol · L-1 · min-1 O2·- production) are continuously infused with concentrations of ·NO equal to or less than the concentration of O2·-, ·NO stimulates lipid peroxidation because of ONOO- formation.21
When the concentration of ·NO exceeds that of
O2·-, lipid peroxidation can
be inhibited by ·NO,22 with a concurrent
formation of nitrated lipid radical termination products.
·NO protects lipids from oxidation by terminating lipid
radical–mediated chain propagation reactions (ie,
ROO·+·NO
ROONO). During
lipid oxidation reactions, the oxidant metabolites of
·NO, namely, ONOO-,
·NO2, nitronium ion
(NO2+), and acidified nitrite
(NO2-/HONO) can also form
nitrated fatty acid and phospholipid derivatives.21 22 23 24
Nitrated forms of
1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine
have been observed after the addition of
S-nitrosoglutathione to liposomes oxidized by soybean
lipoxygenase (LOX).21 Negative-ion
electrospray ionization mass spectrometry (MS) further reveals that
ONOO-,
·NO2, and
NO2+ all react with linoleic
acid (mass-to-charge ratio [m/z] 279) to form a nitrated
linoleate derivative (LNO2, m/z 324).
Tandem mass spectrometry (MS/MS) fragmentation yields a major peak at
m/z 46, indicative of a
NO2- group. A second nitration
product of linoleic acid, m/z 340, forms in the presence
of acidified NO2- (HONO), most
likely in a nitro-epoxyallylic [L(O)NO2]
arrangement.23
Trans-arachidonic acids
(arachidonic acid having 1 trans double bond
and 3 cis double bonds) are also generated after exposure of
all cis-arachidonic acid to
·NO2. These
trans-arachidonic acids are produced by
platelets exposed to ·NO2 and
can be found in human plasma and urine.
14-Nitro-15-hydroxyeicosatrienoic acid is also detected after
·NO2 reaction with
arachidonic acid.24 Thus,
·NO can modify phospholipids and fatty acids to
potentially bioactive products, by forming nitrated lipid
derivatives and altering cis/trans conformations.
·NO-mediated inhibition of lipid peroxidation consumes 2 molecules of ·NO per ROO·.25 With oxidizing linoleic acid, ·NO first reacts with LOO·, where k=2x109 (mol/L)-1 · s-1,25 to form an unstable organic peroxynitrite (LOONO) intermediate that quickly decomposes (k=0.1 to 0.3 s-120 ) to generate an alkoxyl radical (RO·) and ·NO2 as a caged radical pair (RO·-·NO2). Then, a second molecule of ·NO can react with RO· to form an alkyl nitrite, RNO2, where k=2x109 (mol/L)-1 · s-1.26 Other reactions and rearrangements are also possible, yielding derivatives such as epoxyallylic radicals and aldehydes.23 25
·NO Can Modulate Lipid Oxidation by Reacting With
Cellular Pro-Oxidants and Antioxidants
When metals capable of initiating lipid oxidation become
complexed with ·NO to yield metal-nitrosyl derivatives,
lipids can be protected from oxidation. Both the ferrous
(Fe2+) and ferric (Fe3+)
forms of heme proteins can quickly react with ·NO,
where k=107
(mol/L)-1 ·
s-1 and
k=102 to
107
(mol/L)-1 ·
s-1 for ferrous and ferric
forms, respectively,27 thus preventing the formation
of oxidant ·NO metabolites as well as reducing the
redox state of the metal. For example, myoglobin and hemoglobin
oxoferryl species
(·Mb-FeIV=O/·Hb-FeIV=O)
are reduced to their respective ferric (met) forms on reaction with
·NO, protecting against oxidative
damage.28 Additionally, methemoglobin binds
·NO to form a nitrosyl-hemoglobin
(·NO-Hb) intermediate that loses its ability to oxidize
linoleic acid and produce conjugated dienes as well as the ability to
co-oxidize substrates such as ß-carotene.29 In general,
when ·NO complexes with metalloproteins, lipids are
protected from further oxidation by metals and oxidant metabolites of
·NO. However, the relative extent of this reaction in
oxidizing membranes and lipoproteins is unclear, because the rate of
·NO reaction with oxidation-propagating species such as
LOO· is 103- to
107-fold faster.21 25 Because
·NO so potently inhibits lipid
peroxidation–propagating reactions, until ·NO levels
fall below a critical concentration, it is able to protect low
molecular weight antioxidants, eg, 
-tocopherol (-TH),
from oxidation. ·NO then can act cooperatively with
endogenous antioxidants to inhibit lipid oxidation. In
fact, the antioxidant pair ·NO/-TH is more efficient
at inhibiting lipid peroxidation than is
ascorbate/-TH.30
In contrast, oxidant metabolites of ·NO can deplete enzymatic and low molecular weight cellular antioxidants, reducing the likelihood of the termination of free radical lipid propagation reactions. Glutathione peroxidase (GPx), an enzymatic antioxidant, decreases lipid oxidation by reducing hydroperoxides to alcohols. The reactive nitrogen species–producing compounds—S-nitroso-N-acetyl-D,L-penicillamine (SNAP), 3-morpholinosydnonimine-N-ethylcarbamide, and synthetic ONOO-—have all been shown to inhibit GPx.31 32 The inactivation induced by the ·NO donor SNAP involves a multiple-step mechanism, whereas the inactivation by the more powerful oxidant, ONOO-, is an irreversible reaction. This occurs because ONOO- yields more nitrosonium ion (NO+) than does SNAP, with NO+ responsible for oxidizing the active site selenocysteine residue (Sec45) of GPx to a selenenyl sulfide (Se-S) having a free thiol, thereby inactivating the enzyme.32 Once GPx is inhibited, it can no longer scavenge peroxides and terminate propagating lipid oxidation reactions; therefore, lipid oxidation can be expected to increase. In addition to inhibiting GPx, ONOO- also oxidizes low molecular weight plasma antioxidants, including the GPx-reducing cofactor glutathione.33 When ONOO- is added to plasma, ascorbic acid, uric acid, and plasma thiols are depleted, and lipid hydroperoxide derivatives increase. Ascorbic acid is the plasma antioxidant most significantly affected by ONOO-.34 By impairing cellular defenses against lipid oxidation through the depletion of antioxidants and inhibition of GPx, oxidant reactions can greatly increase the rate of lipid peroxidation and lipoprotein modification.
·NO Inhibits LDL Oxidation by Terminating
Radical-Mediated Chain Propagation Reactions
Just as ·NO inhibits the oxidation of purified
lipids, it also inhibits the oxidation of LDL by scavenging
LOO· via chain-terminating interactions of
·NO and other reactive nitrogen species with
LOO·, yielding oxidized and nitrogen-containing lipid
products (A.B. et al, unpublished data, 1999). Pure
·NO, along with the ·NO sources sodium
nitroprusside and SNAP, inhibit LDL oxidation initiated by
Cu2+ or
2',2'-azo-bis(2-amidinopropane)hydrochloride.35
·NO can also inhibit LDL oxidation in cellular systems.
Murine peritoneal macrophages, having iNOS activity stimulated
by interferon-
and lipopolysaccharide, are less capable of
oxidizing LDL than are unstimulated
macrophages.36 37 This lipid protective effect can
be reversed by addition of the NOS inhibitors
NG-aminohomoarginine36
and
NG-monomethyl-arginine.37
When exogenous ·NO is added to unstimulated
macrophages, oxidation of LDL is inhibited.38 In
addition to the inhibition of inflammatory cell–mediated LDL
oxidation, ·NO will also inhibit LDL oxidation mediated
by rabbit aortic endothelial cells.39
Thus, ·NO, derived from either ·NO
donors or iNOS, is able to protect LDL lipid from oxidation induced by
Cu2+, macrophages, and
endothelial cells, thereby potentially limiting
atherogenesis.
Reactive Nitrogen Species Alter the Structure/Function of
LDL
When LDL oxidation is mediated by reactive nitrogen species, the
structures of its proteins and lipids are altered in patterns unique
from non-·NO–dependent (eg, LOO·-
or metal-dependent) oxidation reactions. For example, LDL oxidation by
ONOO- yields nitrated lipid derivatives, such as
nitrated cholesteryl linoleate (LNO2; A.B.
et al, unpublished data, 1999). The tyrosine residues of apoB-100 of
LDL also become nitrated after ONOO--mediated or
NO2-/HOCl-mediated
oxidation.40 41 These ·NO-specific
structural modifications can change the way oxidized LDL (oxLDL)
interacts with endothelial cells and
macrophages (Table 2).
Endothelial cells are protected from oxLDL toxicity in
the presence of ·NO donors.42 However, the
proatherogenic interaction of macrophages and LDL seems to be
amplified when oxidant metabolites of ·NO mediate LDL
oxidation. Low density lipoprotein exposed to reactive nitrogen species
(NO2-LDL) stimulates macrophage uptake
through a specific receptor site41 43 that is neither the
LDL receptor nor the scavenger receptor class A type I.41
Macrophage uptake of NO2-LDL promotes
cholesteryl ester synthesis, intracellular cholesterol and
cholesteryl ester accumulation, and foam cell
formation.40 41 Although ·NO can inhibit
LDL modification by terminating chain-propagating lipid oxidation
reactions, the oxidant-stimulated formation of secondary lipid and
protein structures by oxidant metabolites of ·NO
promotes the proatherogenic uptake of LDL by macrophages.
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·NO Influences Formation of Bioactive Enzymatic Lipid Oxidation Products |
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Reactive nitrogen species can modulate the activity of lipid-oxidizing enzymes such as cytochrome P450 4A,44 12- and 15-LOX, and prostaglandin (PG) endoperoxide synthase (PGHS, or cyclooxygenase). These enzymes metabolize unsaturated fatty acids to bioreactive products, such as prostaglandins, leukotrienes, and thromboxanes. ONOO- can also oxidize arachidonic acid to bioactive F2-isoprostanes in liposomes and LDL.45 46 All of these products can modulate inflammatory reactions and vascular function (Table 3
).
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PGHS-Mediated Metabolism of Arachidonic
Acid Is Modulated by Reactive Nitrogen Species
PGHS catalyzes the initial step in prostaglandin
formation, the oxidation of arachidonic acid to
PGH2. Once formed, PGH2 is
converted by other enzymes to prostaglandins and
thromboxane (TX; Table 3
, Figure 1). PGHS has 2 active sites, a
cyclooxygenase and a peroxidase site. Although the
sites are separate, there is a heme prosthetic group between
these catalytic centers that is required for both activities. The
cyclooxygenase site incorporates 2 molecules of
dioxygen into arachidonic acid to form the hydroperoxy
endoperoxide PGG2, and the
peroxidase site reduces PGG2 to the corresponding
hydroxy endoperoxide,
PGH2.47 To activate the
cyclooxygenase activity, the PGHS heme
prosthetic group first has to be oxidized from
FeIII to
FeIV=O(porphyrin·+) and
then form a tyrosyl radical on Tyr385 via intramolecular electron
transfer. It is this tyrosyl radical intermediate that abstracts an
hydrogen from arachidonic acid, forming a lipid radical
that will react with oxygen. The heme prosthetic group is
typically oxidized by peroxides. There are 2 isoforms of PGHS:
constitutive (PGHS-1) and inducible (PGHS-2). The activities of both
PGHS isoforms can be modulated by ·NO and
ONOO-, acting at different sites in the enzyme
and its catalytic cycle.
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Reactive Nitrogen Species Stimulate Synthesis of PGHS Metabolites
In Vivo and in Cultured Cells
Although alkyl hydroperoxides have been viewed as the preferred
substrate for oxidizing and "activating" the heme
prosthetic group of PGHS,47
ONOO- also readily serves as the oxidizing
substrate. In fact, ONOO- stimulates PGHS
cyclooxygenase activity even in the presence of
hydroperoxide-scavenging reaction systems, such as
glutathione+GPx,47 48 resulting in the proposal that
ONOO- is a central mediator in tissue PGHS
activation mechanisms. For example, the concerted production of
·NO and O2·-
stimulates PGHS activity in RAW264.7 cells,49 supporting
the concept that in systems in which ·NO stimulates the
synthesis of PGHS metabolites (Table 4),
·NO is actually acting as a precursor for
ONOO--mediated PGHS activation.
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Reactive Nitrogen Species Inhibit Synthesis of PGHS Metabolites In
Vivo and in Cultured Cells
Although inhibition of PGHS activity by ·NO (Table 5) is observed in some cell culture
systems, ·NO does not inhibit purified enzyme. In the
presence of arachidonate, ·NO can cause
nitrotyrosine formation at the catalytic Tyr385 of PGHS. However, this
occurs only with concentrations of ·NO that are too
high to be biologically relevant.61 Although
ONOO- is capable of activating PGHS catalytic
activity, it can indirectly decrease the net accumulation of PGHS
metabolites. For example, on stimulation of
ONOO- generation by rat mesangial
cells, there is a concomitant decrease in cellular levels of
PGH2-derived
6-keto-PGF1. ·NO does not
inhibit PGI2 synthesis from
PGH2, thereby supporting
ONOO- as the inhibitor of
PGI2 synthase via nitration of critical tyrosine
residues.62 Although reactive nitrogen species can inhibit
the net accumulation of PGHS metabolites in cell culture, this is most
likely not attributed to the direct inhibition of PGHS.
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Experimental Design Affects Reactive Nitrogen Species–Dependent
Mediation of PGHS
There are several explanations for the opposing effects of
reactive nitrogen species on PGHS activity. These can include
differences in experimental design and ·NO delivery
rates that, in turn, influence the spectrum of ·NO
metabolites being formed. For instance, a ·NO donor may
be used to deliver ·NO to the reaction system, but if
O2·- is being produced in the
cell culture, ONOO- formation could occur and
change the experimental outcome. Additionally, caution must be
exercised when the markers for PGHS activity are based on tissue
accumulation of downstream PGH2 metabolites, such
as PGE2, prostacyclin
(PGI2, including
6-keto-PGF1, a stable
PGI2 metabolite), and TXB2.
Downstream metabolism of PGH2 can introduce
additional opportunities for the modulation of other
eicosanoid-metabolizing enzymes by reactive nitrogen species.
ONOO- inhibition of PGI2
synthase, an enzyme downstream from PGHS, underscores the complications
that can arise from monitoring the extent of formation of only 1 or 2
metabolites and, from this, drawing a global conclusion about the
regulation of PGHS.62 In summary, multiple biologically
relevant mechanisms may underlie the differing influences of reactive
nitrogen species on PGHS activity.
·NO Reaction With LOX
Lipoxygenases are a family of ubiquitously expressed non-heme
iron–containing enzymes that oxidize the unsaturated fatty acids
arachidonate and linoleate to bioactive hydroperoxides and
secondary leukotriene products, thereby increasing
atherogenic lipid oxidation.63 64 65 66 Activation of the
catalytic iron of LOX involves peroxide-mediated oxidation from the
Fe+2 (Ered) to the
Fe+3 (Eox) state. On lipid
substrate binding to the active site, oxygen is stereospecifically
inserted to form a lipid hydroperoxide (LOOH) that then dissociates,
leaving Eox to reinitiate the catalytic cycle
(Figure 2).
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Both pure enzyme–based and cell-based studies reveal that ·NO consistently serves to inhibit LOX. In vitro, ·NO reversibly inhibits soybean LOX type I co-oxidation of ß-carotene in the presence of linoleate.29 The ·NO donor NOC7 inhibits rabbit platelet 12-LOX production of 12-hydroxy-5,8,10,14-eicosatetraenoic acid. However, in the presence of O2·-, ·NO is a less effective inhibitor of platelet 12-LOX, presumably because of the formation of ONOO-, a weak 12-LOX inhibitor.60
Recent studies of mechanisms of ·NO-mediated LOX
inhibition show that formation of
13(S)-hydroperoxyoctadecadienoic acid by soybean and rabbit
reticulocyte 15-LOX is reversibly inhibited by ·NO
(Figure 267 ). Two distinct sites of interaction are
observed between 15-LOX and physiological
concentrations of ·NO (1 to 6 µmol/L). First, on
peroxide activation of 15-LOX, ·NO is consumed (2 mol
·NO per 1 mol 15-LOX). Second, during
dioxygenase turnover, ·NO reacts with
EredLOO· most likely to form an
organic peroxynitrite (LOONO) that decomposes to LOOH and
NO2-. The consumption of
·NO by EredLOO·
partially inhibits 15-LOX by leaving the enzyme in the inactive reduced
state that must be activated again before continuing its
catalytic cycle.67 At higher, nonbiological
·NO concentrations, an inactive ferrous nitrosyl
complex can also form (E-Fe2+-NO) with
Ered.67 68
The concomitant consumption of ·NO by 15-LOX may be of pathophysiological relevance, because ·NO-dependent activation of sGC and the formation of cGMP are also impaired.67 Thus, it can be inferred that when ·NO is consumed by ongoing enzymatic and nonenzymatic lipid oxidation, there are lower steady-state concentrations of ·NO available to mediate vascular relaxation, inhibit platelet aggregation, and modulate production of predominantly proinflammatory arachidonate and linoleate metabolites.
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·NO Protects the Vascular Compartment From Monocyte-Mediated Lipid Oxidation |
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·NO Influences the Development of Atherosclerosis
The impairment of ·NO-mediated endothelial function and the accumulation of oxidized lipids in the vessel wall are central pathological events in atherosclerosis. A myriad of reactions of ·NO with lipids and lipid-oxidizing enzymes (eg, 15-LOX,63 64 65 66 ) have an impact on the chemical reactions and cellular events associated with atherogenesis. Unless it is in an O2·--rich milieu, ·NO tends to limit lipid oxidation processes via reaction with lipid peroxyl radicals,18 nitrosation of redox-active metalloproteins,28 modulation of eicosanoid metabolism,67 and deterring vascular wall infiltration of macrophages.69 70 71 72 Several studies using cholesterol-fed rabbits have demonstrated that ·NO inhibits and may even reverse the progression of atherogenesis. For example, administration of the NOS inhibitor NG-nitro-L-arginine methyl ester leads to significant increases in atherosclerotic lesion formation.73 Also, L-arginine supplementation results in improved vascular relaxation and a decrease in vascular lesion surface area. Interestingly, rates of vascular ·NO production are seen to increase, whereas O2·- generation decreases.74 ·NO produced in vivo by iNOS also protects rat aorta from the development of allograft arteriosclerosis.75 In a rat carotid artery balloon-injury model, endothelial NOS gene transfection restores ·NO production to preinjury levels and inhibits neointimal hyperplasia, further demonstrating the vascular protective effects of ·NO.76 In opposition to the antiatherogenic properties of ·NO displayed in animal models; secondary products of ·NO oxidation, NO2- and ·NO2, lead to proatherogenic LDL modification that promotes the accumulation of intracellular cholesterol and cholesteryl esters along with foam cell formation.41 The contrast between atherogenic properties of ·NO and its oxidant metabolites underscores the difference in function of ·NO production in locations of high oxidant stress versus lower oxidant stress. As long as the concentration of ·NO is higher than that of surrounding oxidants, ·NO is able to maintain a protective role in the vasculature.
·NO Inhibits Proinflammatory Genes
One mechanism underlying the antiatherogenic actions of
·NO is indirect inhibition of lipid oxidation reactions
by ·NO-dependent modulation of cell signal transduction
mechanisms. During an inflammatory response, ·NO can
inhibit the activation of the transcription factor nuclear factor-
B
(NF-B) by inducing expression of the NF-B inhibitor,
IB, and stabilizing the NF-B/IB complex.69
NF-B inhibition causes downregulation of the expression of several
proinflammatory genes that promote interstitial migration
of monocytes and neutrophils, as well as monocyte differentiation
within the vascular compartment. For example, ·NO
inhibits endothelial and smooth muscle cell expression
of adhesion molecules via NF-B during inflammatory reactions,
specifically the expression of intracellular adhesion molecule-1,
vascular cell adhesion molecule-1, and endothelial
leukocyte adhesion molecule-1 (E-selectin).70 71 72 Without
adhesion molecule expression, there is a decrease in the ability of
monocytes and neutrophils to migrate into the vascular wall. Thus,
macrophage accumulation in the arterial intima and
the subsequent oxidation of LDL is reduced. NF-B is also a
transcription factor for the cytokines interleukin-6 and
interleukin-869 and macrophage colony–stimulating
factor (M-CSF),77 all participating in the regulation of
macrophage growth and differentiation. In aortic lesions of
rabbits on high cholesterol diets, M-CSF is found to be
elevated 2-fold.77 Because M-CSF expression is stimulated
by oxLDL, ·NO attenuation of LDL oxidation may thus
indirectly limit the expression of M-CSF. Although the antiatherogenic
roles of ·NO may shift in the extent and mechanism(s)
of action as the disease progresses, ·NO appears to
initially attenuate macrophage-mediated lipid oxidation by
limiting the presence of monocytes within the vascular compartment,
thereby possibly also directly inhibiting proatherogenic oxidative
reactions. Thus, by inhibiting NF-B activation, ·NO
exploits the cascading properties of signaling pathways to protect the
vascular compartment from monocyte-induced lipoprotein oxidation.
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Conclusion |
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There is rapidly evolving insight into the modulation of nonenzymatic and enzymatic lipid oxidation reactions by ·NO, revealing important new non–cGMP-dependent reactivities for this free radical inflammatory and signal transduction mediator. Chemically, ·NO reacts
104-fold faster than does -TH with lipid
peroxyl radicals, suggesting that novel antioxidant properties exist
for ·NO. Indeed, with respect to the inhibition of
lipid oxidation, ·NO and -TH are better cooperative
antioxidant partners than are ascorbic acid and -TH.
·NO is also a potent modulator of LOX and PGHS
activities; this enzyme interaction profoundly affects the rate of
eicosanoid production, local steady-state concentrations of
·NO, and cGMP-dependent signaling reactions mediated by
·NO. Finally, ·NO will inhibit
proinflammatory platelet aggregation, integrin gene expression, and
vessel wall inflammatory cell margination, all leading to a general
attenuation of vascular inflammation and oxidative injury. In the presence of O2·- or peroxidases, ·NO and its oxidation product NO2- can display pathogenic properties on conversion to the reactive oxidizing species ONOO-, ·NO2, and NO2Cl. These species can oxidize and nitrate target molecules, thus generating products with altered structure-function characteristics. In the context of LDL modification, the ·NO-mediated oxidation and nitration of lipid and protein components of LDL are highly proatherogenic because of enhanced macrophage uptake.
The most crucial determinant of the opposing tissue-protective versus proinflammatory manifestations of ·NO reactivity is the underlying oxidative stress of tissues, in particular, the occurrence of accelerated rates of O2·- and H2O2 production, impaired oxidant defenses, and increased peroxidase content. This precept then presents a challenge for the future—the need to develop potent vessel-targeted scavengers of reactive oxygen species so that the salutary actions of ·NO toward signaling events and lipid oxidation reactions are not diverted to more deleterious oxidative reaction pathways.
Received February 16, 2000; accepted March 28, 2000.
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TopAbstractIntroduction{middle dot}NO Biosynthesis and...Oxidative Reactions of {middle...{middle dot}NO-Derived Reactive...{middle dot}NO Influences...{middle dot}NO Protects the...ConclusionReferences |
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1. Moncada S, Higgs EA. Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Invest. 1991;21:361–374.[Medline] [Order article via Infotrieve]
2. Mayer B, Hemmens B. Biosynthesis and action of nitric oxide in mammalian cells. Trends Biochem Sci. 1997;22:477–481. (Erratum. 1998;23:87.)[Medline] [Order article via Infotrieve]
3. Ignarro LJ. Haem-dependent activation of cytosolic guanylate cyclase by nitric oxide: a widespread signal transduction mechanism. Biochem Soc Trans. 1992;20:465–469.[Medline] [Order article via Infotrieve]
4. Lincoln TM, Cornwell TL. Intracellular cyclic GMP receptor proteins. FASEB J. 1993;7:328–338.[Abstract]
5. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526.[Medline] [Order article via Infotrieve]
6.
Liu X, Miller MJS, Joshi MS, Thomas DD, Lancaster
JR Jr. Accelerated reaction of nitric oxide with
O2 within the hydrophobic interior of biological
membranes. Proc Natl Acad Sci U S A. 1998;95:2175–2179.
7. Eich RF, Li TL, Lemon DD, Doherty DH, Curry SR, Aitken JF, Mathews AJ, Johnson KA, Smith RD, Phillips GNJ, et al. Mechanisms of NO-induced oxidation of myoglobin and hemoglobin. Biochemistry. 1996;35:6976–6983.[Medline] [Order article via Infotrieve]
8.
Liao JC, Hein TW, Vaugh MW, Huang K-T, Kuo L.
Intravascular flow decreases erythrocyte consumption of nitric oxide.
Proc Natl Acad Sci U S A. 1999;96:8757–8761.
9.
Vaugh MW, Huang K-T, Kuo L, Liao JC. Erythrocytes
possess an intrinsic barrier to nitric oxide consumption. J
Biol Chem. 2000;275:2342–2348.
10. Kissner R, Nauser T, Bugnon P, Lye PG, Koppenol WH. Formation and properties of peroxynitrite as studied by laser flash photolysis, high-pressure stopped-flow technique, and pulse radiolysis. Chem Res Toxicol. 1997;10:1285–1292. (Erratum. 1998;11:557.)[Medline] [Order article via Infotrieve]
11. Koppenol WH, Kissner R. Can O=NOOH undergo homolysis? Chem Res Toxicol.. 1998;11:87–90.[Medline] [Order article via Infotrieve]
12.
Beckman JS, Koppenol WH. Nitric oxide, superoxide, and
peroxynitrite: the good, the bad, and ugly. Am J
Physiol.. 1996;271:C1424–C1437.
13. Radi R, Denicola A, Freeman BA. Peroxynitrite reactions with carbon dioxide-bicarbonate. Methods Enzymol. 1999;301:353–367.[Medline] [Order article via Infotrieve]
14.
Tien M, Berlett BS, Levine RL, Chock PB, Stadtman ER.
Peroxynitrite-mediated modification of proteins at
physiological carbon dioxide concentration: pH
dependence of carbonyl formation, tyrosine nitration, and methionine
oxidation. Proc Natl Acad Sci U S A. 1999;96:7809–7814.
15. Denicola A, Freeman BA, Trujillo M, Radi R. Peroxynitrite reaction with carbon dioxide/bicarbonate: kinetics and influence on peroxynitrite-mediated oxidations. Arch Biochem Biophys. 1996;333:49–58.[Medline] [Order article via Infotrieve]
16.
Eiserich JP, Cross CE, Jones AD, Halliwell B, van der
Vliet A. Formation of nitrating and chlorinating species by reaction of
nitrite with hypochlorous acid: a novel mechanism for nitric
oxide-mediated protein modification. J Biol Chem. 1996;271:19199–19208.
17.
Van der Vliet A, Eiserich JP, Shigenaga MK, Cross CE.
Reactive nitrogen species and tyrosine nitration in the respiratory
tract. Am J Respir Crit Care Med. 1999;160:1–9.
18. Hogg N, Kalyanaraman B. Nitric oxide and lipid peroxidation. Biochim Biophys Acta. 1999;1411:378–384.[Medline] [Order article via Infotrieve]
19. Patel RP, McAndrew J, Sellak H, White CR, Jo H, Freeman BA, Darley-Usmar VM. Biological aspects of reactive nitrogen species. Biochim Biophys Acta. 1999;1411:385–400.[Medline] [Order article via Infotrieve]
20. Padmaja S, Huie RE. The reaction of nitric oxide with organic peroxyl radicals. Biochem Biophys Res Commun. 1993;195:539–544.[Medline] [Order article via Infotrieve]
21. Rubbo H, Parthasarathy S, Barnes S, Kirk M, Kalyanaraman B, Freeman BA. Nitric oxide inhibition of lipoxygenase-dependent liposome and low-density lipoprotein oxidation: termination of radical chain propagation reactions and formation of nitrogen-containing oxidized lipid derivatives. Arch Biochem Biophys. 1995;324:15–25.[Medline] [Order article via Infotrieve]
22.
Rubbo H, Radi R, Trujillo M, Telleri R, Kalyanaraman B,
Barnes S, Kirk M, Freeman BA. Nitric oxide regulation of superoxide and
peroxynitrite-dependent lipid peroxidation: formation of novel
nitrogen-containing oxidized lipid derivatives. J Biol
Chem. 1994;269:26066–26075.
23. O’Donnell VB, Eiserich JP, Chumley PH, Jablonsky MJ, Krishna NR, Kirk M, Barnes S, Darley-Usmar VM, Freeman BA. Nitration of unsaturated fatty acids by nitric oxide-derived reactive nitrogen species peroxynitrite, nitrous acid, nitrogen dioxide, and nitronium ion. Chem Res Toxicol. 1999;12:83–92.[Medline] [Order article via Infotrieve]
24.
Jiang H, Kruger N, Lahiri DR, Wang D, Vatele J-M.
Nitrogen dioxide induces cis-trans-isomerization of
arachidonic acid within cellular phospholipids.
J Biol Chem. 1999;274:16235–16241.
25. O’Donnell VB, Chumley PH, Hogg N, Bloodsworth A, Darley-Usmar VM, Freeman BA. Nitric oxide inhibition of lipid peroxidation: kinetics of reaction with lipid peroxyl radicals and comparison with alpha-tocopherol. Biochemistry. 1997;36:15216–15223.[Medline] [Order article via Infotrieve]
26. Frost MJ, Smith IWM. Rate constants for the reactions of CH3O and C2H5O with NO over a range of temperature and total pressure. J Chem Soc Faraday Trans. 1990;86:1757–1762.
27. Radi R. Reactions of nitric oxide with metalloproteins. Chem Res Toxicol. 1996;9:828–835.[Medline] [Order article via Infotrieve]
28. Gorbunov NV, Osipov AN, Day BW, Zayas-Rivera B, Kagan VE, Elsayed NM. Reduction of ferrylmyoglobin and ferrylhemoglobin by nitric oxide: a protective mechanism against ferryl hemoprotein-induced oxidations. Biochemistry. 1995;34:6689–6699.[Medline] [Order article via Infotrieve]
29. Kanner J, Harel S, Granit R. Nitric oxide, an inhibitor of lipid oxidation by lipoxygenase, cyclooxygenase and hemoglobin. Lipids. 1992;27:46–49.[Medline] [Order article via Infotrieve]
30.
Rubbo H, Radi R, Anselmi D, Kirk M, Barnes S, Butler J,
Eiserich JP, Freeman BA. Nitric oxide reaction with lipid peroxyl
radicals spares -tocopherol during lipid
peroxidation: greater oxidant protection from the pair nitric
oxide/-tocopherol than
-tocopherol/ascorbate. J Biol Chem. 2000;275:10812–10818.
31.
Asahi M, Fujii J, Suzuki K, Seo HG, Kuzuya T, Hori M,
Tada M, Fujii S, Tamiguchi N. Inactivation of glutathione peroxidase by
nitric oxide: implication for cytotoxicity. J Biol
Chem. 1995;270:21035–21039.
32.
Asahi M, Fujii J, Takao T, Kuzuya T, Hori M, Shimonishi
Y, Taniguchi N. The oxidation of selenocysteine is involved in the
inactivation of glutathione peroxidase by nitric oxide donor.
J Biol Chem. 1997;272:19152–19157.
33.
Radi R, Beckman JS, Bush KM, Freeman BA. Peroxynitrite
oxidation of sulfhydryls: the cytotoxic potential of superoxide and
nitric oxide. J Biol Chem. 1991;266:4244–4250.
34. Van der Vliet A, Smith D, O’Neill CA, Kaur H, Darley-Usmar V, Cross CE, Halliwell B. Interactions of peroxynitrite with human plasma and its constituents: oxidative damage and antioxidant depletion. Biochem J. 1994;303:295–301.
35. Hogg N, Kalyanaraman B, Joseph J, Struck A, Parthasarathy S. Inhibition of low-density lipoprotein oxidation by nitric oxide: potential role in atherogenesis. FEBS Lett. 1993;334:170–174.[Medline] [Order article via Infotrieve]
36. Yates MT, Lambert LE, Whitten JP, McDonald I, Mano H, Ku G, Mao SJ. A protective role for nitric oxide in the oxidative modification of low density lipoproteins by mouse macrophages. FEBS Lett. 1992;309:135–138.[Medline] [Order article via Infotrieve]
37. Jessup W, Dean RT. Autoinhibition of murine macrophage-mediated oxidation of low-density lipoprotein by nitric oxide synthesis. Atherosclerosis. 1993;101:145–155.[Medline] [Order article via Infotrieve]
38. Hogg N, Struck A, Goss SP, Santanam N, Joseph J, Parthasarathy S, Kalyanaraman B. Inhibition of macrophage-dependent low density lipoprotein oxidation by nitric-oxide donors. J Lipid Res. 1995;36:1756–1762.[Abstract]
39. Malo-Ranta U, Yla-Herttuala S, Metsa-Ketela T, Jaakkola O, Moilanen E, Vuorinen P, Nikkari T. Nitric oxide donor GEA 3162 inhibits endothelial cell-mediated oxidation of low density lipoprotein. FEBS Lett. 1994;337:179–183.[Medline] [Order article via Infotrieve]
40. Panasenko OM, Briviba K, Klotz LO, Sies H. Oxidative modification and nitration of human low-density lipoproteins by the reaction of hypochlorous acid with nitrite. Arch Biochem Biophys. 1997;343:254–259.[Medline] [Order article via Infotrieve]
41. Podrez EA, Schmitt D, Hoff HF, Hazen SL. Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest. 1999;103:1547–1560.[Medline] [Order article via Infotrieve]
42. Struck AT, Hogg N, Thomas JP, Kalyanaraman B. Nitric oxide donor compounds inhibit the toxicity of oxidized low-density lipoprotein to endothelial cells. FEBS Lett. 1995;361:291–294.[Medline] [Order article via Infotrieve]
43. Graham A, Hogg N, Kalyanaraman B, O’Leary V, Darley-Usmar V, Moncada S. Peroxynitrite modification of low-density lipoprotein leads to recognition by the macrophage scavenger receptor. FEBS Lett. 1993;330:181–185.[Medline] [Order article via Infotrieve]
44.
Alonso-Galicia M, Drummond HA, Reddy KK, Falck JR,
Roman RJ. Inhibition of 20-HETE production contributes to
the vascular responses to nitric oxide. Hypertension. 1997;29:320–325.
45. Laskey RE, Mathews WR. Nitric oxide inhibits peroxynitrite-induced production of hydroxyeicosatetraenoic acids and F2-isoprostanes in phosphatidylcholine liposomes. Arch Biochem Biophys. 1996;330:193–198.[Medline] [Order article via Infotrieve]
46.
Moore KP, Darley-Usmar V, Morrow J, Roberts LJ II.
Formation of F2-isoprostanes during oxidation of human low-density
lipoprotein and plasma by peroxynitrite. Circ Res. 1995;77:335–341.
47.
Goodwin DC, Landino LM, Marnett LJ. Effects of nitric
oxide and nitric oxide-derived species on prostaglandin
endoperoxide synthase and prostaglandin
biosynthesis. FASEB J. 1999;13:1121–1136.
48.
Goodwin DC, Gunther MR, Hsi LC, Crews BC, Eling TE,
Mason RP, Marnett LJ. Nitric oxide trapping of tyrosyl radicals
generated during prostaglandin endoperoxide
synthase turnover: detection of the radical derivative of tyrosine 385.
J Biol Chem. 1998;273:8903–8909.
49.
Landino LM, Crews BC, Timmons MD, Morrow JD, Marnett
LJ. Peroxynitrite, the coupling product of nitric oxide and
superoxide, activates prostaglandin biosynthesis.
Proc Natl Acad Sci U S A. 1996;93:15069–15074.
50. Salvemini D, Seibert K, Masferrer JL, Misko TP, Currie MG, Needleman P. Endogenous nitric oxide enhances prostaglandin production in a model of renal inflammation. J Clin Invest. 1994;93:1940–1947.
51. Salvemini D, Currie MG, Mollace V. Nitric oxide-mediated cyclooxygenase activation: a key event in the antiplatelet effects of nitrovasodilators. J Clin Invest. 1996;97:2562–2568.[Medline] [Order article via Infotrieve]
52. Motta AB, Gonzalez ET, Rudolph I, Gimeno MF. Regulation of prostaglandin production by nitric oxide in rat smooth muscle myometrial cells: prostaglandins, leukotrienes and essential fatty acids. 1999;60:73–76.
53.
Davidge ST, Baker PN, Laughlin MK, Roberts JM. Nitric
oxide produced by endothelial cells increases
production of eicosanoids through activation of
prostaglandin H synthase. Circ Res. 1995;77:274–283.
54. Manfield L, Jang D, Murrell GA. Nitric oxide enhances cyclooxygenase activity in articular cartilage. Inflamm Res. 1996;45:254–258.[Medline] [Order article via Infotrieve]
55.
Hughes FJ, Buttery LD, Hukkanen MV, O’Donnell A,
Maclouf J, Polak JM. Cytokine-induced
prostaglandin E2 synthesis and
cyclooxygenase-2 activity are regulated both by a
nitric oxide-dependent and -independent mechanism in rat osteoblasts in
vitro. J Biol Chem. 1999;274:1776–1782.
56. Stadler J, Harbrecht BG, Di Silvio M, Curran RD, Jordan ML, Simmons RL, Billiar TR. Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells. J Leukoc Biol. 1993;53:165–172.[Abstract]
57. Minghetti L, Polazzi E, Nicolini A, Creminon C, Levi G. Interferon-gamma and nitric oxide down-regulate lipopolysaccharide-induced prostanoid production in cultured rat microglial cells by inhibiting cyclooxygenase-2 expression. J Neurochem. 1996;66:1963–1970.[Medline] [Order article via Infotrieve]
58. Habib A, Bernard C, Lebret M, Creminon C, Esposito B, Tedgui A, Maclouf J. Regulation of the expression of cyclooxygenase-2 by nitric oxide in rat peritoneal macrophages. J Immunol. 1997;158:3845–3851.[Abstract]
59. Kosonen O, Kankaanranta H, Malo-Ranta U, Ristimaki A, Moilanen E. Inhibition by nitric oxide-releasing compounds of prostacyclin production in human endothelial cells. Br J Pharmacol. 1998;125:247–254.[Medline] [Order article via Infotrieve]
60. Fujimoto Y, Tagano S, Ogawa K, Sakuma S, Fujita T. Comparison of the effects of nitric oxide and peroxynitrite on the 12-lipoxygenase and cyclooxygenase metabolism of arachidonic acid in rabbit platelets. Prostaglandins Leukot Essent Fatty Acids.. 1998;59:95–100.[Medline] [Order article via Infotrieve]
61. Goodwin DC, Landino LM, Marnett LJ. Reactions of prostaglandin endoperoxide synthase with nitric oxide and peroxynitrite. Drug Metab Rev. 1999;31:273–294.[Medline] [Order article via Infotrieve]
62. Zou MH, Klein T, Pasquet JP, Ullrich V. Interleukin 1beta decreases prostacyclin synthase activity in rat mesangial cells via endogenous peroxynitrite formation. Biochem J. 1998;336:507–512.
63. Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, Funk CD. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest. 1999;103:1597–1604.[Medline] [Order article via Infotrieve]
64. Bocan TM, Rosebury WS, Mueller SB, Kuchera S, Welch K, Daugherty A, Cornicelli JA. A specific 15-lipoxygenase inhibitor limits the progression and monocyte-macrophage enrichment of hypercholesterolemia-induced atherosclerosis in the rabbit. Atherosclerosis. 1998;136:203–216.[Medline] [Order article via Infotrieve]
65. Kuhn H, Heydeck D, Hugou I, Gniwotta C. In vivo action of 15-lipoxygenase in early stages of human atherogenesis. J Clin Invest. 1997;99:888–893.[Medline] [Order article via Infotrieve]
66. Sendobry SM, Cornicelli JA, Welch K, Bocan T, Tait B, Trivedi BK, Colbry N, Dyer RD, Feinmark SJ, Daugherty A. Attenuation of diet-induced atherosclerosis in rabbits with a highly selective 15-lipoxygenase inhibitor lacking significant antioxidant properties. Br J Pharmacol. 1997;120:1199–1206.[Medline] [Order article via Infotrieve]
67.
O’Donnell VB, Taylor KB, Parthasarathy S, Kuhn H.
Koesling D, Friebe A, Bloodsworth A, Darley-Usmar VM, Freeman BA.
15-Lipoxygenase catalytically consumes nitric oxide and
impairs activation of guanylate cyclase. J Biol
Chem. 1999;274:20083–20091.
68.
Nelson MJ. The nitric oxide complex of ferrous soybean
lipoxygenase-1: substrate, pH, and ethanol effects on
the active-site iron. J Biol Chem. 1987;262:12137–12142.
69.
Peng HB, Libby P, Liao JK. Induction and stabilization
of I kappa B alpha by nitric oxide mediates inhibition of NF-kappa B.
J Biol Chem. 1995;270:14214–14219.
70.
Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford
RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene
expression and redox-sensitive transcriptional events in human vascular
endothelial cells. Proc Natl Acad Sci
U S A. 1996;93:9114–9119.
71. De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, Liao JK. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96:60–68.
72.
Shin WS, Hong YH, Peng HB, De Caterina R, Libby P, Liao
JK. Nitric oxide attenuates vascular smooth muscle cell activation by
interferon-gamma: the role of constitutive NF-kappa B activity.
J Biol Chem. 1996;271:11317–11324.
73.
Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic
inhibition of nitric oxide production accelerates
neointima formation and impairs endothelial
function in hypercholesterolemic rabbits.
Arterioscler Thromb. 1994;14:753–759.
74.
Candipan RC, Wang BY, Buitrago R, Tsao PS, Cooke JP.
Regression or progression: dependency on vascular nitric oxide.
Arterioscler Thromb Vasc Biol. 1996;16:44–50.
75. Shears LL, Kawaharada N, Tzeng E, Billiar TR, Watkins SC, Kovesdi I, Lizonova A, Pham SM. Inducible nitric oxide synthase suppresses the development of allograft arteriosclerosis. J Clin Invest. 1997;100:2035–2042.[Medline] [Order article via Infotrieve]
76.
Von der Leyen HE, Gibbons GH, Morishita R, Lewis NP,
Zhang L, Nakajima M, Kaneda Y, Cooke JP, Dzau VJ. Gene therapy
inhibiting neointimal vascular lesion: in vivo transfer of
endothelial cell nitric oxide synthase gene. Proc
Natl Acad Sci U S A. 1995;92:1137–1141.
77. Rajavashisth TB, Andalibi A, Territo MC, Berliner JA, Navab M, Fogelman AM, Lusis AJ. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins. Nature. 1990;344:254–257.[Medline] [Order article via Infotrieve]
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