Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1707-1715
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1707.)
© 2000 American Heart Association, Inc.
Nitric Oxide Regulation of Free Radical– and Enzyme-Mediated Lipid and Lipoprotein Oxidation
Allison Bloodsworth;
Valerie B. O’Donnell;
Bruce A. Freeman
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 [O
2·-], 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
(NO
2-) and nitrate
(NO
3-), both of which
are
excreted in the urine. During metabolism to
NO
2-/NO
3-,
·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
(·NO
2; 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) |
where
k=2
x10
6
(mol/L)
-2 ·
s
-1.
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) |
and
 | (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) |
and
 | (5) |
where
k=5.8
x10
4
(mol/L)
-1 · s
-1
at 37°C.
15
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 O
2·-
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,
·NO
2. Second, ·NO
reacts
with O
2·- and
ROO· at nearly diffusion-limited
rates:
k=1.9
x10
10
(mol/L)
-1 ·
s
-110 and
k=1 to 3
x10
9
(mol/L)
-1 ·
s
-120 for
O
2·- 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
O
2·- production)
are
continuously infused with concentrations of ·NO equal
to
or less than the concentration of
O
2·-, ·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
F
2-isoprostanes
in liposomes and
LDL.
45 46 All of these products can modulate
inflammatory
reactions and vascular function (Table 3
).
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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Figure 1. Prostaglandin (PG) and TX
formation. PGHS metabolizes arachidonic acid, forming
PGH2. Other enzymes then convert PGH2 to a
variety of PGs and TX.
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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.
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.
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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Figure 2. ·NO is consumed by enzymatic
turnover of LOX. LH indicates lipid. For further detail on the
products formed from LOONO decomposition, refer to the section
entitled ·NO-Derived Reactive Nitrogen Species
Influence Lipid Oxidation Through Oxidant and Antioxidant
Mechanisms.
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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
O
2·--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
O
2·- 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,
NO
2- and
·NO
2, 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.
|
Conclusion
|
|---|
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
10
4-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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Abstract
Introduction