© 2001 American Heart Association, Inc.
Review |
Interactions Between Nitric Oxide and Lipid Oxidation Pathways
Implications for Vascular Disease
From the Wales Heart Research Institute (V.B.O’D.), University of Wales College of Medicine, Heath Park, Cardiff, Wales, UK; Departments of Anesthesiology, Biochemistry, and Molecular Genetics (B.A.F.), and the Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Ala.
Correspondence to Bruce A. Freeman, PhD, Department of Anesthesiology, 946 Tinsley Harrison Tower, 619 S 19th St, University of Alabama at Birmingham, Birmingham, AL 35233-6810. E-mail bruce.freeman@ccc.uab.edu or o-donnellvb{at}cardiff.ac.uk
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Abstract |
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 Top Abstract IntroductionReactions of NO With...Peroxynitrite-Induced Lipid...Reactions of the {middle...NO-Derived Reactive Species...Catalytic {middle dot}NO...Lipid Oxidation Products...Conclusions: Implications for...References |
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Abstract—Nitric oxide (·NO) signaling pathways and lipid oxidation reactions are of central importance in both the maintenance of vascular homeostasis and the progression of vascular disease. Because both of these pathways involve free radical species that can also react together at extremely fast rates, convergent interactions between these pathways are expected. Biochemical and cell biology studies have defined multiple interactions of ·NO with oxidizing lipids that could lead to either vascular protection or potentiation of inflammatory vascular injury. For example, low levels of ·NO generated by endothelial nitric oxide synthase can terminate propagating lipid radicals and inhibit lipoxygenases, reactions that would be protective. Alternatively, if generated at elevated levels, for example, after inducible nitric oxide synthase expression in inflammation, ·NO can be converted to prooxidant species, such as peroxynitrite (ONOO–) and nitrogen dioxide (·NO2), that can potentiate inflammatory injury to vascular cells. Finally, both enzymatic and nonenzymatic lipid oxidation reactions can influence ·NO bioactivity by directly scavenging ·NO or altering the induction and catalytic activity of nitric oxide synthase enzymes. In this review, we summarize the biochemical interactions between ·NO and lipid oxidation reactions and discuss the recognized and potential roles of these reactions in the vasculature.
Key Words: eicosanoid signaling • lipid • nitric oxide • oxygen • free radical
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Introduction |
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The free radical species ·NO is an endogenously generated mediator of smooth muscle relaxation and inhibitor of platelet/leukocyte activation that is essential for maintenance of vascular homeostasis. In many vascular pathologies, altered ·NO generation rates, often coupled with accelerated ·NO removal through poorly understood pathways, leads to impaired ·NO signaling and secondary generation of toxic ·NO-derived species.1 2 3 4 5 6 Reaction of ·NO with O2·-, yielding peroxynitrite (ONOO–), accounts for a major part of the accelerated ·NO removal2 3 4 5 6 but is not the only mechanism involved, because endothelium-derived relaxing factor (EDRF) activity is often incompletely restored by O2·- scavengers.7 8 9 This suggests that the reaction of ·NO with other biochemical "sinks" can also account for enhanced rates of EDRF consumption. Further evidence for alterations in ·NO metabolism in vascular disease is provided by observations of the tyrosine oxidation/nitration product 3-nitrotyrosine (NO2-tyr) and elevations in inducible nitric oxide synthase (iNOS or NOS2) activity. For example, both NO2-tyr and NOS2 expression are consistently elevated clinically (transplant coronary artery disease, atherosclerotic lesions, cardiac allograft rejection, and myocardial inflammation) and in animal models of vascular disease (hypercholesterolemia-induced atherosclerosis, balloon-injured arteries, ischemic heart injury, and myocardial inflammation) (reviewed in Reference 1010 ; see also References 1111 –17).
Increased lipid oxidation is a characteristic feature of inflammatory vascular diseases and has been suggested to sometimes play a causative role, although this has not been conclusively proven.18 19 20 21 22 23 24 The candidate mechanisms that generate oxidized lipids in vivo are numerous and include metal-dependent Fenton oxidation, enzyme-catalyzed oxidation by lipoxygenase (LOX) or myeloperoxidase (MPO), reaction with hypochlorous acid (HOCl), cell-dependent oxidation via a diversity of O2·- and H2O2-generating oxidases, and, finally, oxidation by ·NO-derived reactive species (eg, ·NO2, nitryl chloride [NO2C], and ONOO–).25 26 27 28 29 30 31 32 In particular, support for a pathogenic role of LOX-catalyzed lipid oxidation in vivo in atherogenesis includes the observations that functional 15-LOX and its products are present in human and rabbit lesions,21 33 34 disruption of the mouse 12/15-LOX gene diminishes atherosclerosis in apoE-deficient mice, and inhibition of 15-LOX prevents development of atherosclerosis in cholesterol-fed rabbits.35 36 In contrast, targeted overexpression of rabbit macrophage 15-LOX prevents diet-induced atherosclerosis.37
In the vasculature, nitric oxide (·NO) and lipid oxidation signaling pathways can potentially interact at several levels. Because of the diversity of the biochemical pathways involved, an understanding of how these processes might impact on vascular homeostasis is important. In this review, we summarize current knowledge of how lipid oxidation pathways and ·NO-derived species interact at a chemical and cellular level and describe what is known about how these interactions might influence disease progression.
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Reactions of NO With Purified Lipids, Lipoproteins, and Membranes |
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NO potently inhibits lipid oxidation in a variety of in vitro model systems, including unsaturated free fatty acid emulsions, phosphatidylcholine liposomes or LDL oxidized by Cu2+, azo initiators of LOO· formation, ONOO–, endothelial cells, or macrophages.30 31 38 39 40 41 42 This is primarily a consequence of ·NO reacting with lipid-derived radicals (eg, L·, LO·, and LOO·) via diffusion-limited rates (109 to 1011 [mol/L]–1 · s–1) to terminate lipid peroxidation propagation reactions.38 40 43 44 45 46 47 48 49 50 During the reaction of LOO· with ·NO, two molecules of ·NO are consumed as the primary organic peroxynitrite (LOONO) intermediate rapidly decomposes (t1/2=0.2 to 0.6 second) to secondary radical species that reacts further.38 For example, LOONO can decompose to caged radicals [LO· ·NO2], which can either terminate after rearrangement of LO· to an epoxide, L(O)NO2, or dissociate and react with additional ·NO (Figure 1
). Alternatively, LOONO can hydrolyze to LOOH and
NO2–. The small
molecular radius and hydrophobicity of ·NO
facilitates partitioning into hydrophobic membrane
compartments,51 thus
enhancing the efficacy of ·NO to terminate
lipid peroxidation. The fast rate of reaction between
LOO· and ·NO
(2x109
[mol/L]–1 · s–1),
compared with 
-tocopherol (1 to 5x105
[mol/L]–1 · s–1,
with rate depending on the alkyl chain length and charge
characteristics of the LOO· species),
allows ·NO to spare tocopherol during
lipid peroxidation and predicts that steady-state
·NO concentrations of 30 nmol/L will
outcompete endogenous -tocopherol concentrations (20 µmol/L) for
termination of
LOO·.38
In addition, the reduction of topheroxyl radical by ascorbate is less
effective at preventing lipid oxidation–induced tocopherol loss than
the reaction of ·NO with
LOO·.52
These comparisons underscore the profound capacity of
·NO for antioxidant reactions in the
vasculature. It is emphasized that these properties of
·NO can be manifested only if alternative
prooxidative reactions (eg, ·NO reaction
with O2·- to yield
ONOO–) do not predominate. NO-mediated
termination of lipid radicals can also limit secondary lipid
oxidation–mediated processes that are involved in vascular injury,
including nuclear factor-
B(NF-B) activation, the linkage of
vascular cell adhesion molecule-1 (VCAM-1) gene expression with NF-B
activation, lung injury secondary to intestinal ischemia, pulmonary
epithelial cell oxygen injury, and the cytotoxicity of
H2O2 and alkyl
hydroperoxides.53 54 55 56 57 58 59
Finally, ·NO can undergo reactions with
O2 and/or
O2·- to yield
oxidizing and nitrating species that also cause
·NO-dependent cytotoxicity in vitro
through inducing lipid oxidation.
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Peroxynitrite-Induced Lipid Oxidation and Nitration |
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Peroxynitrite is unique as a lipid oxidant, because it mediates peroxidation of unsaturated fatty acids in the absence of transition metal catalysts.29 Peroxynitrite is more than two orders of magnitude more potent than H2O2 in catalyzing lipid oxidation in vitro and, in contrast to transition metal catalysts, mediates LDL oxidation even in the presence of lipophilic antioxidants.60 In vitro, ONOO– oxidizes diverse classes of lipids (eg, purified fatty acids, neutral lipids and phospholipids, and lipophilic antioxidants and LDL lipids) forming conjugated diene, malondialdehyde, lipid peroxide, lipid hydroxide, F2-isoprostane, and oxysterol products.29 44 50 60 61 62 63 In the case of LDL, this results in an LDL derivative recognized by the macrophage scavenger receptor.64 In addition to oxidizing lipids, ONOO– mediates linoleate and LDL cholesteryl linoleate nitration to the derivative LNO265 (also A. Bloodsworth and B.A. Freeman, unpublished data, 2001). This reaction proceeds via either hydrogen abstraction by ·NO2 or addition mechanisms involving NO2+ (Figure 2
). A role for ONOO– in
initiating lipid oxidation in atherosclerosis has been
suggested66 ; however, this
requires that the barrier of competing reactions with thiols be
overcome, which are present intracellularly at concentrations of up to
10 mmol/L
(k=5.9x103
[mol/L]–1·s–1
for ONOO– reaction with
cysteine).
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Reactions of the ·NO Metabolites ·NO2 and NO2Cl With Unsaturated Lipids |
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Several reactive nitrogen species derived from ·NO oxidize and nitrate unsaturated fatty acids and their methyl/ethyl esters in vitro. Nitrogen dioxide will both oxidize and nitrate unsaturated lipids, with nitration occurring by hydrogen abstraction and addition reactions.28 65 67 68 69 70 71 72 73 74 These reactions result in formation of a complex mixture of products including nitrated lipid derivatives and alkylnitrites, including those shown in Figure 3
.75
Nitration of methyl linoleate and linolenate by
·NO2 proceeds via
initial hydrogen abstraction to form a carbon-centered alkyl radical,
which at low oxygen tensions combines with
·NO2 to form
allylic nitro compounds
(Figure 2
). The yield of oxygen-containing lipid products
(eg, LOOH, LOH, etc) formed by
·NO2 oxidation thus
depends on the concentration of O2 that will
facilitate peroxidation
reactions.28 At high
O2 concentrations, for example, in lung lining
fluid, ·NO2 will
predominantly mediate lipid oxidation. Conversely, at low
O2 tension (eg, within an inflamed hypoxic organ
or microvessel), nitration reactions may preferentially occur. Somewhat
analogous to ·NO,
·NO2 can also react
at diffusion-limited rates with peroxyl and alkoxyl radicals, leading
to inhibition of peroxidation and formation of novel N-containing lipid
derivatives.46 76
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The oxidation of nitrite
(NO2–) by
MPO-derived hypochlorous acid (HOCl) will yield nitryl chloride
(NO2Cl),77 78
which, in purified LDL, depletes ß-carotene and -tocopherol,
initiates lipid oxidation, forms
3-nitrotyrosine,27 and can
yield an LDL particle similar to that found in foam cells. The direct
oxidation of NO2– by
MPO+H2O2 yields
·NO2 and also
oxidizes LDL lipids to a proatherogenic
particle.79 80 81
Oxidation and nitration of membrane lipids by MPO may be operative in
atherogenesis, because products of MPO activity are found in vascular
lesions25 82 ;
however, this has not been conclusively proven. Finally, acidification
of NO2– forms
nitrous acid (HONO), which decomposes to nitrosating and nitrating
species including N2O3
and ·NO2. Reaction
of ethyl linoleate with HONO yields several nitrated lipids, including
nitroalkenes and nitroalcohols, whereas reaction of lipid
hydroperoxides (LOOH) with HONO forms
nitroepoxylinoleate65 75
(Figure 4). Formation of HONO is favored at pH<4; therefore,
if these reactions are to occur in the vasculature, they will require
acidic microenvironments, for example, in the phagolysosomes of
neutrophils or macrophages.
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NO-Derived Reactive Species Modulate the Activity and Expression of Lipid Oxidation Enzymes |
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Enzymes such as LOX, prostaglandin endoperoxide H synthase (PGHS), and cytochrome P450 (CYP) that oxidize lipids to bioactive eicosanoids play critical signaling roles in the regulation of vascular cell function and inflammatory responses and are ubiquitously expressed by virtually all vascular cells under both physiological and inflammatory conditions (Figure 5
). Generally, lipid oxidation by these enzymes
involves formation of enzyme-bound radical intermediates, including
lipid alkyl (L·) and peroxyl
(LOO·) radical species. Free peroxyl or
alkyl radicals react with ·NO at
diffusion-limited rates. Thus, reaction of
·NO with enzyme-bound lipid radicals will
modulate rates of eicosanoid product formation and decrease
bioavailable concentrations of ·NO, as
discussed
below.46 47 48 49
In addition to lipid radicals, these enzymes form several other
intermediates that can react with NO during turnover, including amino
acid or porphyrin radicals and various redox states of iron. In the
next sections, the known interactions of
·NO with the various enzyme intermediates
formed during catalysis are discussed.
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Prostaglandin Endoperoxide H Synthase
(PGHS)
Prostaglandins are generated via arachidonate
oxygenation by PGHS, of which there are both constitutive (PGHS-1:
stomach, gut, kidney, and platelets) and inducible (PGHS-2: fibroblasts
and macrophages) isoforms. Under inflammatory conditions, both NOS2 and
PGHS-2 expression is upregulated in tandem by proinflammatory cytokines
including interleukin-1 (IL-1) and tumor necrosis factor, indicating
that high levels of both prostaglandin and
·NO will be produced in concert in
vivo.83 84 85 86 87 88 89 90 91 92
Reactive nitrogen species have multiple effects on PGHS activity. Purified PGHS-1 is not significantly inhibited by ·NO; however, in several cell types, including endothelial cells and platelets, ·NO highly stimulates prostaglandin production.93 94 95 96 In other cell types, ·NO suppresses lipopolysaccharide (LPS)-induced PGHS-2 expression, resulting in apparent enzyme inhibition.97 98 Finally, in NOS2 knockout mice, less urinary prostaglandin E2 is found, although platelets from these animals generate more thromboxane B2 in vitro.99
NO can interact in several ways with PGHS, by forming an
Fe-nitrosyl complex, acting as a peroxidase-reducing substrate,
directly terminating the catalytic tyrosyl radical in the enzyme active
site, and theoretically, by termination of enzyme-bound lipid
radicals93 100 101 102
(Figure 6). Formation of the nitrosyl complex of PGHS by
·NO is favored for the ferrous form,
whereas the
Kd for
formation of the ferric ·NO complex is
very high, being 0.92 mmol/L for
·NO.102
Because the ferrous enzyme is not involved in enzyme catalysis and
nonbiological (mmol/L) concentrations of
·NO would be required for significant
metal center reaction to occur, nitrosyl complex formation is unlikely
to be a mechanism of PGHS activity modulation by
·NO in vivo. Although termination of
tyrosyl radicals by ·NO proceeds at
essentially diffusion-limited rates, it is intriguing that PGHS is not
more readily inhibited in vitro by ·NO.
Possible explanations are that ·NO-tyrosyl
radical reactions are readily reversible, or by acting as a
peroxidase-reducing substrate, ·NO
alternatively contributes to enzyme
activation.93 103
Peroxynitrite is also an oxidizing-peroxidase substrate for both PGHS-1
and PGHS-2, suggesting that ·NO could
activate prostaglandin synthesis under inflammatory conditions where
O2·- production is
abundant.104 105
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Lipoxygenases (LOX)
Lipoxygenases are non-heme iron–containing enzymes
that catalyze oxidation of arachidonate or linoleate to bioactive lipid
hydroperoxides. In mammalian cells, at least three isoforms are known
with the best characterized, 5-LOX, found mainly in
leukocytes.106 12-LOX
isoforms are present in platelets and
monocytes.107 108
15-LOX is expressed in reticulocytes during maturation into
erythrocytes, where it plays a central role in intracellular membrane
degradation. In human monocytes, expression of 15-LOX is induced by
IL-4 and
IL-13.109 110 A
role for 15-LOX in the initiation and progression of atherosclerosis
has also been suggested by the observation of 15-LOX products at
elevated levels in atherosclerotic
lesions.21 22 34 111
Lipoxygenases contain a single non-heme iron that alternates
between Fe2+ and
Fe3+ during catalysis. Resting enzyme
predominantly exists as the reduced form, requiring oxidation by
hydroperoxides before dioxygenation can occur. Inhibition of LOX
(soybean, rabbit and human 15-LOX, and human platelet 12-LOX) by
·NO has been
reported43 112 113 114 115
and was proposed to result from formation of an Fe-nitrosyl complex
with the ferrous enzyme. However, metal center reaction only occurs at
high and nonphysiological ·NO
concentrations,116 117 118 119
making this pathway of LOX inhibition unlikely. Rather, tissue LOX
inhibition results from a termination reaction between
·NO and the enzyme-bound lipid peroxyl
radical
(EredLOO·),43
which would be expected to occur at nanomolar concentrations of
·NO present in vivo. After this reaction,
dissociation and hydrolysis of the organic peroxynitrite (LOONO) gives
LOOH and NO2– as
products
(Figure 7). Because the LOX catalytic cycle is not completed,
reoxidation of the enzyme-bound iron is
required.43 Thus, because
·NO reaction occurs after
O2 insertion into the fatty acid substrate, the
LOX product profile is unchanged, the rate of product generation is
suppressed, and ·NO is
consumed.
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Cytochrome P450 (CYP)
CYP enzymes are a ubiquitously expressed family
of heme proteins that play major roles in xenobiotic metabolism and
lipid oxidation. Nonhepatic CYP arachidonate metabolites also act as
intracellular signaling molecules in vascular tissue. For example, the
CYP4A product 20-hydroxyeicosatetraenoic acid (20-HETE) is a
potent vasoconstrictor whose generation in vascular smooth muscle cells
is inhibited by
·NO.120
A second product, 11,12-EET, is produced by endothelial cells, avidly
esterified into endothelial phospholipid pools, and mediates vascular
relaxation, possibly accounting for a component of the presently
undescribed endothelium-derived hyperpolarizing factor
activity.121 122 123
Preformed EETs in endothelial membranes can influence vascular function
by altering membrane characteristics, ion transport, or lipid-dependent
signaling pathways.124 For
example, one isomer, 5,6-EET, mediates vasodilation by either
increasing ·NO production through
stimulating Ca2+ influx into endothelial
cells125 or by directly
activating smooth muscle Kca
channels.121 126
NO has been shown to inhibit the CYP enzymes thromboxane synthase and
prostacyclin synthase in vitro. This can have a significant effect on
vascular function, in that these enzymes generate thromboxane and
prostacyclin, eicosanoid mediators that are central in regulation of
platelet aggregation and smooth muscle tone in
vivo.127 Formation of
nitrosyl complexes has been observed for some CYP isoforms; however,
the detailed mechanisms by which ·NO
interacts with CYP have not been
elucidated.
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Catalytic ·NO Consumption by Lipid Oxidation Enzymes |
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PGHS and LOX catalyze ·NO consumption via reaction with intermediates formed during enzyme turnover, a reaction first confirmed using purified enzymes and isolated vascular cells, including platelets and monocytes43 103 (also M.J. Coffey and V.B. O’Donnell, unpublished data, 2001). In these cell models, the rates and amounts of ·NO consumed are high, relative to expected rates and amounts of ·NO generated, suggesting that these reactions might play a role in both physiological and pathological ·NO removal in vascular cells.
Studies of soybean LOX-1, purified rabbit reticulocyte
15-LOX, human 15-LOX in murine fibroblast PA317 cells, and porcine
leukocyte 12-LOX in monocytes have shown that the reaction of
·NO with
EredLOO· results in
turnover-dependent ·NO
consumption43 (also
M.J. Coffey and V.B. O’Donnell, unpublished data, 2001). This
scavenging of ·NO effectively prevents
activation of purified or monocyte soluble guanylyl cyclase
(sGC), indicating that enzyme-bound lipid radicals can compete with the
heme of sGC for ·NO binding and thus
attenuate the bioactivity of ·NO in
mammalian cells
(Figure 8A).43
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Through acting as a peroxidase-reducing substrate,
·NO is also consumed rapidly by both
purified PGHS-1 plus arachidonate and by the A23187 or
thrombin-activated PGHS-1 activity of human
platelets.103 Rates of
·NO removal by platelets are fast enough
to deplete micromolar ·NO levels and
potently prevent ·NO-dependent activation
of platelet sGC, thus causing platelets to overcome the antiaggregatory
effects of ·NO
(Figure 8B). This reveals a second novel proaggregatory
function for PGHS-1 in addition to its generation of proaggregatory
eicosanoids—specifically, catalytic consumption of the antiaggregatory
species ·NO.
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Lipid Oxidation Products Regulate NO Bioactivity |
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Although ·NO production regulates the induction and activity of lipid oxidation enzymes, their eicosanoid products can conversely modulate rates of cellular ·NO production. In platelets, activation of nitric oxide synthase is inhibited by aspirin or indomethacin, an effect that is overcome by addition of thromboxane A2.128 In the murine macrophage cell line J774, induction of NOS2 by LPS is inhibited by indomethacin,129 inferring involvement of PGHS products. Activation of LOX also leads to increases in NOS2 expression. For example, the nonspecific LOX inhibitor nordihydroguaiaretic acid prevents induction of NOS2 in myocytes or smooth muscle by IL-1 or LPS, respectively.130 131 In addition, isolated peritoneal macrophages from 12-LOX knockout mice display 50% less NO2–+NO3- generation after interferon-
/LPS
challenge.132 Finally,
oxidized LDL can have opposing effects on
·NO bioactivity, either through
lysolecithin-dependent impairment of endothelium-dependent arterial
relaxation or by causing induction of
NOS2.133 134 |
Conclusions: Implications for Vascular Disease |
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NO and ·NO-derived reactive species interact with lipid oxidation pathways via multiple mechanisms in vitro that are only recently being revealed. Because both processes are central to vascular regulation, an understanding of the particular interactions that are involved in pathogenesis of vascular disease in vivo is important. A role for ·NO acting as an antioxidant in vivo by inhibiting proatherogenic lipid oxidation is suggested, because increasing ·NO bioactivity through l-arginine supplementation has been successful in attenuating vascular dysfunction in hypercholesterolemic rabbits.135 136 137 In humans, results have been mixed, with intravenous infusion of l-arginine acutely improving coronary vasodilation but having no effect on microvascular endothelial function in patients with hypercholesterolemia.138 An alternative successful strategy has been to lower steady-state concentrations of ·NO-inactivating reactive oxygen species in animal models, via supplementation with antioxidant enzymes and oxidant scavengers.139 140 141 142 143 144 Several isoforms of PGHS and LOX are upregulated in both clinical and experimental cases of vascular disease,21 34 145 146 147 148 149 150 151 with inhibition of these enzymes normalizing blood pressure in some cases.150 152 153 154 Our observations of catalytic ·NO consumption by PGHS and LOX indicate novel mechanisms by which these enzymes might contribute to blood pressure regulation, in addition to the generation of vasoactive prostanoids. These are the first demonstrations of controlled ·NO removal by regulated catalytic processes in mammalian cells. Recent studies using iNOS knockout mice demonstrated altered urinary prostaglandin E2 levels, confirming direct interactions between ·NO signaling and PGHS pathways in vivo.99 Finally, the reactions of ·NO and ·NO-derived species (eg, ·NO2 or ONOO–) with oxidizing lipids leads to generation of novel nitrated lipid derivatives. If formed in atherosclerotic lesions, these species will either act as novel ·NO donors or possess distinct signaling properties similar to eicosanoids (A. Bloodsworth, V.B. O’Donnell, and B.A. Freeman, unpublished data, 2001).
Currently, knowledge regarding interactions between lipid oxidation pathways and ·NO is mainly from in vitro and animal model studies. Although great progress has been made at that level, a challenge for the future is to more incisively define which reactions are involved in the maintenance of vascular homeostasis and the initiation and progression of clinical vascular diseases.
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Acknowledgments |
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This work was supported by the British Heart Foundation (V.B.O’D.) and National Institutes of Health Grants RO1-HL64937, RO1-HL58115, and P6-HL58418 (B.A.F). V.B.O’D. is a Wellcome Trust RCD Fellow.
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Footnotes |
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Original received September 13, 2000; revision received October 26, 2000; accepted November 10, 2000.
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References |
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