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© 2000 American Heart Association, Inc.
Brief Reviews |
Oxidation of LDL by Myeloperoxidase and Reactive Nitrogen Species
Reaction Pathways and Antioxidant Protection
From the Linus Pauling Institute, Oregon State University, Corvallis.
Correspondence to Balz Frei, PhD, Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512. E-mail balz.frei{at}orst.edu
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Abstract |
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 Top Abstract IntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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Abstract—Oxidative modification of low density lipoprotein (LDL) appears to play an important role in atherogenesis. Although the precise mechanisms of LDL oxidation in vivo are unknown, several lines of evidence implicate myeloperoxidase and reactive nitrogen species, in addition to ceruloplasmin and 15-lipoxygenase. Myeloperoxidase generates a number of reactive species, including hypochlorous acid, chloramines, tyrosyl radicals, and nitrogen dioxide. These reactive species oxidize the protein, lipid, and antioxidant components of LDL. Modification of apolipoprotein B results in enhanced uptake of LDL by macrophages with subsequent formation of lipid-laden foam cells. Nitric oxide synthases produce nitric oxide and, under certain conditions, superoxide radicals. Numerous other sources of superoxide radicals have been identified in the arterial wall, including NAD(P)H oxidases and xanthine oxidase. Nitric oxide and superoxide readily combine to form peroxynitrite, a reactive nitrogen species capable of modifying LDL. In this review, we examine the reaction pathways involved in LDL oxidation by myeloperoxidase and reactive nitrogen species and the potential protective effects of the antioxidant vitamins C and E.
Key Words: low density lipoproteins • myeloperoxidase • reactive nitrogen species • vitamin C • vitamin E
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Introduction |
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TopAbstractIntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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The hypothesis that oxidative stress plays an important role in the pathogenesis of atherosclerosis has gained considerable support. Although there are many determinants in the development of an atherosclerotic lesion, substantial in vitro evidence links LDL oxidation to potentially atherogenic processes at the molecular and cellular level.1 2 3 However, the in vivo mechanism(s) of the initiation and progression of LDL oxidation is presently unclear and is a topic of much research. The most relevant information concerning this mechanism has come from immunohistochemical and biochemical analyses of animal and human atherosclerotic lesions and lipoproteins extracted from these lesions. Ceruloplasmin, 15-lipoxygenase, myeloperoxidase (MPO), and inducible (in addition to endothelial) nitric oxide synthase (NOS) have been found in animal and human lesions and can cause or contribute to LDL oxidation in vitro.2 4 5 6 7 8 9 10
With respect to a role for ceruloplasmin in in vivo LDL oxidation, specific markers of metal ion–catalyzed protein damage are not elevated in early or intermediate lesions, in contrast to advanced lesions.9 11 Immunohistochemical detection of aldehyde-modified LDL in human and animal lesions12 13 also has been used as evidence for metal ion–mediated oxidation; however, the specificity of antibodies raised against aldehyde-modified or copper-oxidized LDL has been questioned, because these can cross-react with LDL modified by hypochlorous acid (HOCl).14 Therefore, it appears unlikely that ceruloplasmin and other sources of redox-active metal ions contribute significantly to LDL oxidation in vivo during the early stages of atherosclerotic lesion development.
The role of 15-lipoxygenase in LDL oxidation and atherogenesis is controversial, because the mechanism by which the intracellular enzyme "seeds" extracellular LDL with hydroperoxides is unclear.15 16 Furthermore, there is limited evidence for the presence of 15-lipoxygenase–modified lipids in lesions, because only small increases in the S/R enantiomeric ratio of lipid hydro(pero)xides were detected.17 18 Nevertheless, immunohistochemical studies have demonstrated the presence of 15-lipoxygenase in macrophage-rich regions of human and rabbit atherosclerotic lesions,19 20 and epitopes of oxidized LDL colocalize with 15-lipoxygenase.20 Interestingly, cholesterol-fed transgenic rabbits overexpressing the human 15-lipoxygenase gene in macrophages develop significantly less atherosclerosis than do their nontransgenic littermates.21 In contrast, 12/15-lipoxygenase–knockout mice crossbred with atherosclerosis-prone apoE-deficient mice exhibit significantly reduced lesion development.22 The lack of agreement between these studies is intriguing and indicates that more studies are needed to determine the role of 15-lipoxygenase in LDL oxidation and atherogenesis.
MPO and MPO-derived HOCl have been implicated in in vivo LDL
modification and atherogenesis (Figures 1
and 2).23 Immunoreactive and
catalytically active MPO has been detected in human atherosclerotic
lesions and colocalizes with macrophages.10 In
addition, specific markers of MPO- and HOCl-mediated protein
modification, ie, dityrosine and 3-chlorotyrosine, have been isolated
from human atherosclerotic lesions.9 24 Similarly,
epitopes recognized by antibodies against HOCl-modified proteins have
been detected in early and advanced human lesions.25
Interestingly, the extent of atherosclerosis was
increased in LDL-receptor–deficient MPO-knockout mice fed a high fat
diet compared with MPO wild-type mice.26 However, it is
not known whether MPO and MPO- or HOCl-modified proteins are
present in atherosclerotic lesions of mice and contribute to
atherogenesis. In vitro studies have shown that HOCl-modified LDL
stimulates foam cell formation,27 28 enhances leukocyte
oxidant and cytokine production, degranulation,
migration, and adherence to endothelial cells, and
increases vascular cell permeability.29 30 31 These
pathophysiological properties of HOCl-modified LDL
toward leukocytes and vascular cells could contribute to the
development of atherosclerosis. In addition, we have
found that, like mildly oxidized LDL,32 HOCl-modified LDL
impairs the activity of lecithin:cholesterol
acyltransferase, a key component of the antiatherogenic reverse
cholesterol transport (McCall, Carr, and Frei,
unpublished data, 1999).
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Although nitric oxide (NO·) has been
implicated as an antiatherogenic molecule,33 34 the
reactive nitrogen species (RNS) formed by the reaction of
NO· with oxygen and superoxide are potentially
proatherogenic (Figure 2
). Inducible NOS has been detected in
lesions,7 8 as has the reaction product of RNS with
protein tyrosine residues, 3-nitrotyrosine.7 8 35 36
3-Nitrotyrosine, detected immunocytochemically, was localized to
macrophages, foam cells, and smooth muscle
cells.7 8 35 Interestingly, 3-nitrotyrosine was detected
even in the presence of extracellular superoxide
dismutase,7 suggesting that the enzymatic dismutation of
superoxide cannot effectively compete with the formation of
peroxynitrite in vivo.37 One study reported that the
levels of 3-nitrotyrosine are significantly higher in LDL derived from
atherosclerotic intima than in LDL isolated from plasma,36
although another study found no difference in 3-nitrotyrosine levels
between atherosclerotic lesions and normal intima.38 LDL
modified in vitro by RNS is recognized by the macrophage
scavenger receptor39 and thus may contribute to foam cell
formation.
Thus, several lines of evidence indicate that MPO and RNS contribute to atherogenic modification of LDL in vivo.7 8 9 10 24 25 In the present review, we examine the reaction pathways involved in LDL oxidation by these 2 mechanisms and the potential protective effects of the antioxidant vitamins C and E.
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MPO-Dependent Oxidation of LDL |
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TopAbstractIntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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MPO is a heme-containing enzyme secreted by human phagocytes after activation by respiratory burst stimulants.40 MPO has 2 major activities: halogenation and peroxidation (reactions 1 through 4). During the halogenation activity of MPO, hydrogen peroxide (H2O2) reacts with native MPO to form the redox intermediate compound I, which oxidizes halides to hypohalous acids via a 2-electron oxidation step (reactions 1 and 2). HOCl is the major strong oxidant generated by the MPO system of stimulated phagocytes at physiological concentrations of halide ions.40 MPO also oxidizes a number of organic substrates (RH) to free radical intermediates by a classical peroxidase cycle involving compounds I and II (reactions 3 and 4). Reactions 1 through 4 are as follows:
 | (1) |
 | (2) |
 | (3) |
 | (4) |
In vitro reaction of reagent or MPO-derived HOCl with LDL results
primarily in modifications of apoB, with little oxidation of the lipids
(Table 1).27 41 HOCl reacts
readily with the 
-amino groups of apoB lysine residues, resulting in
the formation of N-chloramines (reactions 5 and 6), which
are quantitatively the major products in HOCl-modified
LDL.27 LDL-associated chloramines have been shown to
alter LDL charge characteristics, leading to the uncontrolled uptake of
HOCl-modified LDL by macrophages in
culture.27 28 41 A small proportion of the LDL-associated
chloramines break down to form aldehydes,41 42 which may
be involved in the cross-linking and aggregation of HOCl-exposed LDL
particles via Schiff base formation, as well as the formation of
advanced glycation end products.41 Other amino acid
residues of apoB, such as cysteine, methionine, tryptophan, and
tyrosine, are also susceptible to oxidation by reagent or MPO-derived
HOCl.27 Among the latter amino acid residues and lysine,
cysteine and methionine exhibit the highest reactivity with HOCl (Table 1).41 43 Although tyrosine is only a minor target,
one of its products, namely, 3-chlorotyrosine, is a useful specific
biomarker of HOCl-mediated protein modification.24
Reactions 5 and 6 are as follows:
 | (5) |
 | (6) |
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Several investigators have reported lipid peroxidation in isolated LDL exposed to reagent or MPO-derived HOCl, but the amounts of lipid oxidation products formed were small.41 44 45 One mechanism proposed by Panasenko46 involves homolytic cleavage of preformed lipid hydroperoxides by HOCl to generate alkoxyl radicals. More recently, it has been reported that LDL-associated chloramines break down to produce radicals that can initiate lipid peroxidation.47 Formation of chlorinated lipids in LDL exposed to MPO has also been reported and has been proposed to be due to the formation of molecular chlorine.48 However, chlorinated lipids are only minor products of MPO-mediated reactions with LDL.
MPO can also modify LDL via reactive amino acid intermediates.
MPO-derived tyrosyl radicals, produced by 1-electron oxidation of free
tyrosine (see reactions 3 and 4),49 can initiate LDL lipid
peroxidation and dityrosine formation (Table 1)50
as well as catalyze oxidative cross-linking of proteins.51
However, because tyrosine is present in plasma at levels several
orders of magnitude lower than chloride ions (20 to 80 µmol/L
versus 100 to 140 mmol/L, respectively),52 it is
uncertain whether significant amounts of tyrosyl radicals are formed by
MPO in the presence of physiological concentrations
of chloride ions. Reaction of MPO-derived HOCl with free amino acids
produces N-chloramine derivatives, which subsequently can
break down to form reactive aldehydes (Figure 1).53 Reactive aldehydes derived from tyrosine
and serine have been shown to modify protein lysine
residues.54 55 Although N-chloramines are less
reactive than HOCl, we have found that stable N-chloramine
derivatives of N
-acetyl-lysine and
taurine, as well as ammonia, still retain sufficient oxidizing capacity
to oxidize apoB cysteine residues.56
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Antioxidant Protection Against MPO-Dependent LDL Modification |
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TopAbstractIntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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Vitamin E (
-tocopherol), the major
lipid-soluble antioxidant in LDL, and the carotenoids ß-carotene and
lycopene are susceptible to HOCl-mediated LDL oxidation, but only at
relatively high concentrations of HOCl.27 42
LDL-associated ubiquinol, in contrast, is fully oxidized with
physiological (200 µmol/L) concentrations of
HOCl.27 In vitro supplementation of LDL with vitamin E
does not protect against HOCl-mediated modification of the
lipoprotein57 and may actually enhance lipid oxidation via
-tocopheroxyl radical–mediated abstraction of bis-allylic hydrogens
from unsaturated lipids.47 Similarly, vitamin E is unable
to protect LDL lipids from oxidation by tyrosyl radicals generated by
the MPO/H2O2/tyrosine
system.50 As such, vitamin E does not appear to provide
effective antioxidant protection against MPO-mediated modification of
LDL, most likely a result of apoB being the major target of HOCl and
the ability of vitamin E to promote in vitro lipid oxidation in the
absence of suitable co-antioxidants.58
One likely defense against MPO-mediated LDL oxidation is vitamin C
(ascorbate), an important water-soluble antioxidant in biological
fluids (Figure 1).59 Vitamin C scavenges HOCl in a
stoichiometric manner (reaction 7)60 and can regenerate
amines from HOCl-derived N-chloramines (reaction
8).27 56 Moreover, as a co-antioxidant, vitamin C can
prevent the pro-oxidant properties of the -tocopheroxyl radical
(reaction 9).58 We found that
physiological concentrations of vitamin C can
protect LDL lysine and tryptophan residues from oxidation by HOCl and
partially protect LDL cysteine residues.56 We also
observed that vitamin C protects against LDL cysteine loss mediated by
N-acetyl-lysine-, taurine-, and
mono-chloramines; protection occurred to different extents depending on
the type and hydrophobic tendencies of the chloramine
used.56 Reactions 7 through 9 are as follows:
 | (7) |
 | (8) |
 | (9) |
Although generation of HOCl by the MPO/H2O2/Cl- system (reactions 1 and 2) produces similar modifications to LDL as reagent HOCl,41 the interaction of vitamin C in the enzymatic system may be complex in view of the fact that vitamin C not only scavenges HOCl and N-chloramines (reactions 7 and 8) but can also paradoxically enhance the chlorinating activity of MPO.61 62 The latter activity of vitamin C involves regeneration of the native enzyme from the compound II intermediate (reaction 4), which is catalytically inactive in the chlorination reaction. The predominant effect of vitamin C most likely depends on its concentration, with catalytic (low micromolar) concentrations stimulating enzymatic activity and higher concentrations scavenging HOCl and chloramines. Although vitamin C reacts with compound I of MPO at a rate similar to that of chloride ions [reaction 3, k2=1.1x106 (mol/L)-1 · s-1, versus reaction 2, k2=4.7x106 (mol/L)-1 · s-1, respectively],63 64 vitamin C is unlikely to act as a competitive inhibitor of HOCl formation by MPO because of its relatively low physiological plasma concentration compared with that of chloride ions (25 to 150 µmol/L versus 100 to 140 mmol/L, respectively).65
Vitamin C also protects against LDL lipid peroxidation initiated by
MPO-derived tyrosyl radicals.50 66 This is likely due to
vitamin C’s scavenging of these radicals (reaction 10) or possibly
preventing their formation by MPO, because the rate constants of the
reaction of vitamin C and tyrosine with compounds I and II are
comparable63 64 and because their extracellular
concentrations are similar (20 to 80 µmol/L versus 25 to
150 µmol/L, respectively).52 65 In addition,
because tyrosyl radical–mediated lipid peroxidation is presumably
mediated via an -tocopheroxyl radical intermediate,58
vitamin C could also be acting as a co-antioxidant in this system (see
reaction 9). Thus, vitamin C appears to provide efficient antioxidant
protection from HOCl- and MPO-mediated damage to LDL in vitro by a
number of mechanisms (reactions 7 through 10). Reaction 10 is as
follows:
 | (10) |
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Oxidation of LDL by RNS |
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TopAbstractIntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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Nitric oxide (nitrogen monoxide, NO·) is an important regulatory molecule in vascular homeostasis.67 NO· is synthesized from L-arginine by the NADPH-dependent enzyme NOS (reaction 11), which is present as constitutive or inducible isoforms in several cell types, including endothelial cells and phagocytes, respectively.67 NO· itself is a relatively unreactive radical, but it readily interacts with molecular oxygen and superoxide radicals to produce a multitude of RNS.68 Potential sources of superoxide in the arterial wall include xanthine oxidase, cyclooxygenases, NAD(P)H oxidases, leakage from the mitochondrial respiratory chain,69 and, under certain conditions, NOS itself.70 Reaction 11 is as follows:
 | (11) |
The reaction of NO· with oxygen
[k3=6x106
(mol/L)-2 · s-1]71
is thought to lead to the formation of the nitrosating intermediate
dinitrogen trioxide (N2O3,
reaction 12), which can convert amines and thiols into, respectively,
nitrosamines (reaction 13) and S-nitrosothiols (reaction
14), an important "storage" form of NO·.
68 Reducing agents, such as ascorbate, have been
implicated in the rapid release of NO· from
S-nitrosothiols (reaction 15).72 73 74
Reactions 12 through 15 are as follows:
 | (12) |
 | (13) |
 | (14) |
 | (15) |
The reaction of NO· with superoxide, a
diffusion-limited radical-radical reaction
[k2=1.9x1010
(mol/L)-1 · s-1],37
produces peroxynitrite and peroxynitrous acid
(pKa 6.5, reaction 16).37
Peroxynitrite mediates oxidation and nitration reactions, although the
intermediate(s) involved is as yet unidentified; this is possibly an
activated isomer (*ONOOH) rather than the products of
homolytic cleavage, ie, hydroxyl radical (·OH)
and nitrogen dioxide (NO2·),
as originally suggested.75 Peroxynitrite also reacts with
carbon dioxide present in biological fluids
[k2=5.8x104
(mol/L)-1 · s-1,
reaction 17] to form reactive intermediates that can oxidize thiols
and nitrate phenolic compounds, such as tyrosine.68
Reactions 16 and 17 are as follows:
 |
 |
In vitro experiments have shown that NO· produces very little, if any, modification of LDL particles, as determined by antioxidant consumption, lipid peroxidation, and electrophoretic properties.76 77 78 79 To the contrary, numerous studies have shown that NO· inhibits oxidation of LDL by copper ions, aqueous peroxyl radicals, lipoxygenases, and macrophages.76 80 81 82 83 84 85 86 One mechanism proposed for this antioxidant activity is the rapid reaction of NO· with lipid peroxyl radicals [k2=1.3x109 (mol/L)-1 · s-1) to form nonradical adducts, thus terminating the lipid peroxidation chain reaction.82
In the presence of oxygen or superoxide,
NO· forms RNS (reactions 12 and 16) that can
modify LDL in vitro (Table 2).76 77 78 The sydnonimine
compound SIN-1, which breaks down to simultaneously
generate NO· and superoxide, is often used as
an in vitro source of peroxynitrite.87 Exposure of LDL to
reagent peroxynitrite or SIN-1 results in depletion of vitamin E and
ß-carotene88 89 and oxidation of lipids to lipid
hydroperoxides, F2-isoprostanes, and
oxysterols.76 77 90 91 Specific amino acid residues of
apoB are also modified, including lysine, tryptophan, and
cysteine92 93 ; modification of the lysine and cysteine
residues is probably due to secondary reactions with lipid-derived
aldehydes and radicals, respectively.93 Interestingly,
bicarbonate was found to increase LDL oxidation by peroxynitrite (Table 2),88 92 most likely acting via reaction 17 above.
These data suggest that bicarbonate-containing biological fluids could
enhance peroxynitrite-mediated damage in vivo.
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MPO and RNS |
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TopAbstractIntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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Although 3-nitrotyrosine was initially used as a specific biomarker for peroxynitrite formation, this notion has been questioned recently, because MPO can also generate 3-nitrotyrosine via RNS (see below).94 95 NO· itself may modulate the activity of MPO because NO· reacts rapidly with the iron center of a number of heme-containing proteins and enzymes, resulting in either activation (eg, guanylate cyclase) or inactivation (eg, cytochrome P-450).68 Peroxynitrite has also been shown to interact with MPO, converting the enzyme to its compound II form.96
Recent work has indicated that peroxidases can convert nitrite, a
physiological oxidation product of
NO· (reaction 12),68 into RNS, most
likely nitrogen dioxide
(NO2·, reaction
18).97 The
MPO/H2O2/nitrite system,
presumably via NO2·
production, modifies apoB and lipids in LDL (Table 2),98 99 resulting in increased uptake of the
modified LDL by macrophages in culture.98 HOCl can
also react with nitrite to form nitryl chloride
(NO2Cl, reaction 19), which can chlorinate and
nitrate tyrosine residues100 as well as oxidize LDL lipids
and antioxidants (Table 2).101 However, nitryl
chloride is unlikely to be formed from nitrite in vivo because of the
presence of higher concentrations of alternative targets that are more
reactive with HOCl, particularly thiols.102 Because RNS,
such as NO2·, can be formed
by MPO at physiological concentrations of nitrite
and chloride ions,98 99 these could contribute to the
formation of nitrated (lipo)proteins in vivo.94 95 It
should be noted, however, that HOCl may cause the loss of
3-nitrotyrosine103 and thus result in an underestimation
of the levels of this biomarker at sites where HOCl and RNS are being
produced. Reactions 18 and 19 are as follows:
 |
 | (19) |
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Antioxidant Protection of LDL Against RNS |
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TopAbstractIntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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Vitamins C and E may protect LDL from atherogenic modifications mediated by RNS (Figure 2
). A recent study showed that in vitro
enrichment of LDL with vitamin E decreased or increased
peroxynitrite-mediated lipid peroxidation, depending on the
peroxynitrite to LDL ratio; at ratios <100:1, vitamin E acted as a
pro-oxidant, whereas at ratios >200:1, vitamin E acted as an
antioxidant.92 Vitamin E enrichment did not protect
against peroxynitrite-induced lysine or tryptophan loss. In contrast,
vitamin C inhibited protein and lipid oxidation and prevented
consumption of vitamin E.92
Vitamin E is able to partially protect LDL lipids from oxidation by RNS
generated by the
MPO/H2O2/nitrite
system,50 suggesting that -tocopherol is
acting as a chain-breaking antioxidant. In contrast, vitamin C
scavenges peroxidase-generated nitrating species97 and
effectively inhibits LDL oxidation by the
MPO/H2O2/nitrite
system.99 It should be noted, however, that the reaction
of NO2· with vitamin C
regenerates nitrite (reaction 20),97 suggesting that
vitamin C is acting as a competitive inhibitor rather than
a radical scavenger. Thus, based on the in vitro findings discussed
above, vitamin C may be able to prevent the oxidation of LDL by
reactive oxygen, chlorine, and nitrogen species generated in vivo; in
contrast, vitamin E would be expected to be less effective and
sometimes may act as a pro-oxidant in LDL. Reaction 20 is as
follows:
 | (20) |
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Conclusions and Perspectives |
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TopAbstractIntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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As discussed in the present brief review, in vitro and in vivo studies have linked MPO and RNS to the oxidative, and thus atherogenic, modification of LDL. In light of the efficacy of plasma and interstitial fluid antioxidants, in particular, vitamin C, to quench reactive oxygen, chlorine, and nitrogen species,59 104 it appears that localized microenvironments in which antioxidant defenses have been overwhelmed may, in part, underlie the focal nature of atherosclerosis. Defining this intimal microenvironment, however, has proven difficult, as illustrated by the recent observations that relatively large amounts of vitamins C and E coexist with oxidized lipids in human atherosclerotic lesions.105 106
Future progress in defining the oxidative pathways involved in atherogenesis and evaluating effective strategies to limit oxidative damage are dependent on the resolution of conceptual and methodological problems. The limited number of stable and mechanism-specific biomarkers of oxidative damage has hindered the characterization of the precise pathway(s) involved in LDL oxidation in vivo. Additional impediments to research in the area include the ubiquitous nature of in vitro transition metal contamination, the continued use of relatively insensitive and nonspecific indices of LDL oxidation, eg, thiobarbituric reactive substances, and artifactual ex vivo formation of lipid hydroperoxides during LDL isolation and storage. In addition, the various forms of oxidized LDL generated in vitro need to be carefully characterized.
Understanding the specific pathway(s) of LDL oxidation in vivo is essential for evaluating whether a causal link exists between LDL oxidation and atherosclerotic lesion development, as the "oxidative modification hypothesis" of atherosclerosis postulates. Moreover, if such a link exists, understanding these pathways is requisite for the design of specific strategies to inhibit LDL oxidation and its pathobiological and clinical sequelae. If, as current evidence suggests, MPO and RNS are involved in atherogenesis through the oxidative modification of LDL, then dietary or supplemental vitamin C should prove useful as an antiatherogenic agent.
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Acknowledgments |
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The authors are supported by grants from the US National Institutes of Health (HL-56170 to B.F.) and the American Heart Association (No. 9920420Z to A.C.C.). We thank Jace Carson for graphic design.
Received December 7, 1999; accepted April 14, 2000.
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TopAbstractIntroductionMPO-Dependent Oxidation of LDLAntioxidant Protection Against...Oxidation of LDL by...MPO and RNSAntioxidant Protection of LDL...Conclusions and PerspectivesReferences |
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 J. Galle Oxidative stress in chronic renal failure Nephrol. Dial. Transplant., November 1, 2001; 16(11): 2135 - 2137. [Full Text] [PDF]
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A. MERTENS and P. HOLVOET Oxidized LDL and HDL: antagonists in atherothrombosis FASEB J, October 1, 2001; 15(12): 2073 - 2084. [Abstract] [Full Text] [PDF]
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 M. Meydani Vitamin E and Atherosclerosis: Beyond Prevention of LDL Oxidation J. Nutr., February 1, 2001; 131(2): 366S - 368. [Abstract] [Full Text]
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A. Frustaci, J. Kajstura, C. Chimenti, I. Jakoniuk, A. Leri, A. Maseri, B. Nadal-Ginard, and P. Anversa Myocardial Cell Death in Human Diabetes Circ. Res., December 8, 2000; 87(12): 1123 - 1132. [Abstract] [Full Text] [PDF]
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A. C. Carr, B.-Z. Zhu, and B. Frei Potential Antiatherogenic Mechanisms of Ascorbate (Vitamin C) and {alpha}-Tocopherol (Vitamin E) Circ. Res., September 1, 2000; 87(5): 349 - 354. [Abstract] [Full Text] [PDF]
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S. Kotamraju, N. Hogg, J. Joseph, L. K. Keefer, and B. Kalyanaraman Inhibition of Oxidized Low-density Lipoprotein-induced Apoptosis in Endothelial Cells by Nitric Oxide. PEROXYL RADICAL SCAVENGING AS AN ANTIAPOPTOTIC MECHANISM J. Biol. Chem., May 11, 2001; 276(20): 17316 - 17323. [Abstract] [Full Text] [PDF]
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