© 1995 American Heart Association, Inc.
Articles |
Formation of F2-Isoprostanes During Oxidation of Human Low-Density Lipoprotein and Plasma by Peroxynitrite
From the Department of Clinical Pharmacology (K.P.M.), Royal Postgraduate Medical School, London; Biochemical Sciences (V.D.-U.), Wellcome Research Laboratories, Beckenham, Kent, England; and the Department of Clinical Pharmacology (J.M., L.J.R.), Vanderbilt Medical Center, Nashville, Tenn.
Correspondence to Dr Kevin Moore, Department of Medicine, Royal Free Hospital School of Medicine, Pond St, London NW3 2QQ, UK.
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Abstract |
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Abstract F2-Isoprostanes are novel bioactive prostaglandin F2–like compounds produced by nonenzymatic free radical–catalyzed peroxidation of arachidonic acid. F2-Isoprostanes are initially formed in situ on phospholipids and subsequently released. Quantification of the F2-isoprostanes has been found to represent a valuable and reliable marker of lipid peroxidation. Oxidative modification of low-density lipoprotein (LDL) is a key process for the recognition of LDL by the scavenger receptors on macrophages. The oxidative mechanism responsible for the modification of LDL in vivo remains unclear, but an attractive candidate is the powerful oxidant peroxynitrite, which can be formed by reaction of nitric oxide and superoxide in the vessel wall. To further explore the potential role of peroxynitrite in the oxidative modification of plasma lipids, we investigated whether incubation of LDL and plasma with peroxynitrite or SIN-1, which decomposes to form nitric oxide and superoxide, catalyzes the formation of F2-isoprostanes. Incubation of LDL with peroxynitrite (0.125 to 1 mmol/L) or SIN-1 (0.5 and 1 mmol/L) induced a concentration-dependent increase in the formation of F2-isoprostanes, reaching a maximum of 5.5±2.05-fold (SEM) and 18.2±4.0-fold above control values, respectively. The increase of F2-isoprostanes induced by SIN-1 was essentially completely inhibited by superoxide dismutase. Incubation of plasma with peroxynitrite or SIN-1 yielded similar results. These results indicate that peroxynitrite can induce the formation of F2-isoprostanes in lipoproteins. Since F2-isoprostanes can exert potent biological activity such as vasoconstriction, they may contribute to the vascular pathobiology associated with atherosclerosis.
Key Words: atherosclerosis • nitric oxide • superoxide • peroxynitrite • isoprostanes
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The oxidative modification of LDL is now thought to be one of the key events in the pathogenesis of atherosclerosis.1 2 3 4 5 Associated with LDL oxidation is the modification of the apolipoprotein (apo) B protein of LDL and the generation of a wide range of lipid-derived oxidation products including hydroperoxides and aldehydes,4 5 6 which ultimately convert the LDL particle to a form recognized by the macrophage scavenger receptor.7 8 9 It is now clear that oxidized LDL may itself elicit a number of biological responses that could contribute to the pathogenesis of atherosclerosis. For example, oxidized LDL inhibits the expression of the genes coding for interleukin-1 and tumor necrosis factor in isolated macrophages, inhibits NO generation, and promotes endothelin-1 synthesis from endothelial cells.9 10 11 12 13 14 15 16 It has also been shown that oxidized LDL is chemotactic for monocytes and macrophages, cytotoxic to fibroblasts and endothelial cells, and can induce smooth muscle cell proliferation. It is likely that the formation of macrophage-derived foam cells in atherosclerotic lesions arises from attempts by this cell to detoxify the decomposition products of lipid peroxidation. In support of this idea, we have shown that treatment of macrophages with oxidized LDL leads to a transitory depletion of glutathione followed by an induction of glutathione synthesis, and the resulting enhanced levels are essential in preventing the cytotoxicity of oxidized LDL to the cells.17 18
When this protective pathway is overwhelmed, the lipid decomposition
products can presumably accumulate locally and exert various
biological effects. It is well recognized that stereospecific oxidation
of arachidonic acid by the lipoxygenase
and cyclooxygenase enzymes may contribute to the
inflammatory component of
atherosclerosis.19
Approximately 10% of the unsaturated fatty acid in LDL
is arachidonic acid,20 which is converted
to a multitude of oxidation products, the pharmacological
properties of which are largely unknown. The recently described
F2-isoprostanes are an important exception to this. These
are a family of prostaglandins formed by nonenzymatic free
radical–catalyzed peroxidation of arachidonyl-containing
phospholipids.21 22 23 The oxidation of
arachidonic acid forms a series of bicyclic
endoperoxide intermediates, which then are reduced to
prostaglandin F2 (PGF2)–like
compounds. Fig 1
illustrates the formation of four
PGF2 regioisomers, each of which theoretically can be
composed of eight diastereoisomers. In contrast to enzymatic
prostanoid formation, the generation of these compounds is not affected
by cyclooxygenase inhibitors, and the
prostanoid moiety is formed intact within phospholipids.23
These compounds have been shown to be formed in several animal models
of oxidant stress and during certain human pathological
processes.24 25 However, one of the major
F2-isoprostanes formed, namely
8-iso-PGF2
, has been shown to be a very potent
vasoconstrictor, probably acting via a unique receptor similar to but
distinct from the thromboxane receptor.26 27 28 Since
the biological activity of the other F2-isoprostanes is
unknown, the net effect of a mixture of this complex series of
molecules on vascular function cannot be predicted. It is evident from
Fig 1 that any process capable of initiating oxidation of
arachidonic acid could in principle result in the
formation of F2-isoprostanes. Indeed, we have recently
shown that F2-isoprostanes can be formed in vitro during
the oxidation of plasma or isolated human LDL by either copper or azo
initiators, which generate peroxyl radicals,29 and these
results have recently been confirmed by Gopaul and
colleagues.30 Although free metals such as iron, copper,
or hemoproteins are potential oxidants that may come into play after
tissue damage, they are unlikely to be involved in the initial stages
of atherogenesis. Until recently, the identification of plausible
nonenzymatic mechanisms that could lead to oxidation of lipids in vivo
has proved difficult.
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This problem is highlighted by the fact that several studies21 22 25 have now shown that there is a consistent but low level of endogenous F2-isoprostanes present in the plasma lipids of normal volunteers and elevated in subjects who smoke.31 The process initiating lipid peroxidation in these circumstances must function under conditions that are extremely effective in suppressing lipid peroxidation mediated by metals or hemoproteins. We have proposed an alternative mechanism involving the reaction of the two free radicals NO and superoxide in the artery wall to form the powerful oxidant peroxynitrite, which is capable of oxidizing lipids even in the presence of high concentrations of plasma antioxidants.32 33 34 35 36 37 Considerable indirect evidence has been reported for the simultaneous generation of NO and superoxide in the vasculature including the antiatherogenic and antihypertensive effects of the enzyme SOD.35 36 37 The properties of peroxynitrite as an oxidant relevant to atherosclerosis include its ability to oxidize lipids32 33 38 and sulfhydryl groups in plasma39 40 and release copper from ceruloplasmin41 and nitrate tyrosine residues.42
In the present study, we have investigated the hypothesis that oxidation of LDL or plasma lipids, initiated by the simultaneous production of the free radicals superoxide and NO, causes the formation of F2-isoprostanes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation and Characterization of Human LDL
Human LDL was isolated from plasma from individual donors by differential centrifugation, using the method described previously.43 After dialysis against calcium- and magnesium-free PBS containing NaCl (140 mmol/L), KCl (2.7 mmol/L), Na2HPO4 (8.13 mmol/L), KH2PO4 (1.47 mmol/L), and EDTA (10 µmol/L), the LDL was sterilized by filtration through a 0.22-µm filter and stored at 4°C until used. The protein concentration was measured using the BCA protein assay (Pierce) and was typically 1 to 2 mg/mL.
Oxidation of LDL
All oxidation experiments were carried out in duplicate at a
final concentration of LDL of 200 µg/mL in PBS. A total of 50 or 100
µg of LDL was used in each experiment, and five preps from different
donors were used. To initiate the oxidation reactions, peroxynitrite or
SIN-1 was added to the LDL and incubated at 37°C until the time
specified.
Peroxynitrite was prepared in a quenched flow reactor as previously
described and stored as a stock solution of 250 mmol/L at 4°C at pH
11 to 12 until used.44 The concentration of available
peroxynitrite was measured on the day of the experiment by its
absorbance at 302 nm using an extinction coefficient (
) of 1670
mol/L-1 · cm-1.45
Peroxynitrite is very unstable at physiological pH.
Control experiments were therefore carried out in which peroxynitrite
was diluted in PBS, left at room temperature for 10 minutes, and then
added to the incubation mixture at a final concentration of 1 mmol/L.
This mixture is termed "decomposed peroxynitrite." All
experiments were carried out in the presence of DTPA
(diethylene-triamine-penta-acetic acid, 100 µmol/L) to chelate any
free iron–contaminating solutions during oxidation reactions. The
concentration of EDTA in the experiments in which LDL was exposed to
oxidants varied from 1 to 2 µmol/L, depending on the particular
preparation used. Since contaminating metals such as copper or iron are
present in the buffers at concentrations lower than 1 µmol/L, the
100 µmol/L DTPA would effectively chelate these metals in a nonredox
active form and inhibit chelation by EDTA. SIN-1 was obtained from
Casella, AG, and dissolved in PBS for use. The concentrations used (0.5
and 1 mmol/L) were selected on the basis of a pilot study and chosen to
yield the maximal production of F2-isoprostanes.
SOD (bovine erythrocyte, Sigma) was used at 100 U/mL. After incubation,
the oxidation reactions were quenched by addition of BHT to a final
concentration of 10 µmol/L.
Oxidation of Plasma Lipids
Blood was collected from three volunteers into EDTA (final
concentration, 0.27%), and peroxynitrite or SIN-1 was added as above
to duplicate 3-mL samples of plasma, up to a final volume of 3.3 mL.
The samples were incubated overnight at 37°C and the reaction
terminated with BHT (10 µmol/L).
Extraction and Measurement of
F2-Isoprostanes
Esterified F2-isoprostanes were quantitated
after base hydrolysis as the free F2-isoprostanes, after
purification and derivatization, by selected ion monitoring gas
chromatography negative ion chemical ionization/mass
spectrometry.46 In brief, the lipids were extracted by
adding 2 vol of Folch reagent (chloroform and methanol at a 2:1 ratio,
containing BHT at 10 µmol/L). After vortex mixing and
centrifugation, the organic layer was aspirated, dried
under nitrogen, and stored at -80°C until assay. All samples were
treated and extracted in duplicate. After addition of the internal
standard ([2H4]-PGF2,
Cayman Co), base hydrolysis, extraction, and TLC purification,
compounds were analyzed as pentafluorobenzyl ester,
trimethysilyl ether derivatives monitoring the M-181 ions,
m/z 569 for endogenous
F2-isoprostanes, and m/z 573 for
[2H4]-PGF2. The
F2-isoprostanes elute as a series of
chromatographic peaks over 20 seconds, and quantitation is
based on the primary peak eluting 7 seconds before the internal
standard.46
Electrophoretic Mobility of LDL
Oxidation of LDL is associated with an increase in
electrophoretic mobility, due to oxidation of the apo B.
Electrophoretic mobility of LDL was determined on 0.5% agarose gels
after 30 minutes at 100 V in 0.05 mol/L barbital buffer, pH 8.6, with
the use of a lipoprotein electrophoresis system (Beckman Co). Gels were
fixed and stained with Sudan black B and all results related to
mobility of the control sample in each gel.32
Statistics
Levels of F2-isoprostanes in the samples treated
with either peroxynitrite or SIN-1 were compared with baseline
untreated control values using the nonparametric
Mann-Whitney U test and were considered significant when the
value was P<.05. All statistics were carried out using the
absolute values rather than the N-fold increase expressed in the
graphs. Where mean values are used, the standard error of the mean is
also quoted. Correlations between changes in electrophoretic mobility
and F2-isoprostane generation were carried out using the
Spearman rank correlation test.
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Results |
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Oxidation of LDL and Formation of F2-Isoprostanes by Peroxynitrite
Incubation of LDL with peroxynitrite at a concentration range of 125 to 1000 µmol/L overnight (
20 hours) increased electrophoretic
mobility of the LDL (data not shown) and increased formation of
F2-isoprostanes in a concentration-dependent manner (Fig 2 and Table). At the highest
concentration used (1 mmol/L peroxynitrite), esterified
F2-isoprostanes increased by 2- to 13-fold from a mean
baseline value of 2.64±0.95 ng/mg of LDL (P<.05), and
electrophoretic mobility increased from 1.0 to 1.52±0.09
(P<.01). In contrast, there was no change in
F2-isoprostane formation or the electrophoretic mobility
when LDL was incubated with decomposed peroxynitrite. When the results
of all five LDL preps were grouped together, there was no correlation
with REM. However, there was a significant individual correlation of
F2-isoprostanes with REM for four of the five LDL
preparations used (P<.01 to .02) (Fig 3).
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Peroxynitrite is labile at acid or neutral pH, and the initial reaction
with LDL is likely to be completed within a very short period
(seconds). To determine whether the F2-isoprostanes were
formed during the initial oxidation reaction or as a consequence of the
chain propagation reaction initiated by peroxynitrite, we assessed the
time dependency of this process in a single experiment and the effect
of adding the chain-breaking antioxidant BHT 5 minutes after addition
of peroxynitrite in four preparations. All of the peroxynitrite will be
decomposed within this 5-minute period, and if the
F2-isoprostanes were formed immediately, then BHT would
have no effect and the amount of F2-isoprostanes formed
should remain constant after the initial reaction. On the other hand,
if peroxynitrite initiates a chain propagation lipid peroxidation
reaction, then this should be suppressed by the delayed addition of
BHT. There was a progressive and marked increase in
F2-isoprostane formation from a baseline value of 0.3 ng/mg
LDL, increasing to 0.67 ng/mg LDL at 4 hours and 2.05 ng/mg LDL at 24
hours (n=1). In contrast, the electrophoretic mobility of LDL showed an
increase from 1.0 to 1.48 at 30 minutes, with values of 1.47 at 4 hours
and 1.69 at 24 hours. Furthermore, addition of BHT 5 minutes after
peroxynitrite completely inhibited the formation of
F2-isoprostanes induced by peroxynitrite (n=4). In
contrast, there was still a small increase in electrophoretic mobility
(1.0 to 1.15±0.03) after addition of peroxynitrite and BHT,
consistent with an immediate oxidation of the apo B component
of LDL and indicating no direct scavenging of peroxynitrite by BHT (Fig 2
and Table). The observation that the increase of REM to 1.15 was less
than that observed in the absence of BHT (1.0 to 1.52±0.09) does,
however, suggest that part of the increase in electrophoretic mobility
is due to chain propagation reactions within the lipid phase of the
particle.
Oxidation of LDL and Formation of F2-Isoprostanes
by SIN-1
SIN-1 spontaneously decomposes to form both NO and superoxide
anion in aqueous solution and yields a continuous source of an oxidant
with the characteristics of peroxynitrite over several
hours.47 Incubation of LDL with SIN-1 (0.5 to 1 mmol/L)
significantly increased formation of esterified
F2-isoprostanes by 8- to 31-fold (mean, 19-fold) and
electrophoretic mobility by 1.8-fold (Fig 4 and Table).
When compared with electrophoretic mobility (Fig 4), it is clear that
the level of isoprostane formation is approximately 3- to 4-fold higher
than that found with peroxynitrite (Figs 2 and 3). The formation of
F2-isoprostanes by SIN-1 was inhibited by coincubation with
SOD (100 U/mL).
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Oxidation of Human Plasma by Peroxynitrite and SIN-1
Incubation of plasma with peroxynitrite or SIN-1 yielded results
similar to those observed with LDL. Esterified
F2-isoprostanes increased in all plasma samples incubated
with either peroxynitrite or SIN-1 (n=3) (Fig 5). The
mean increase in baseline values was 2.3-fold for peroxynitrite and
19.7-fold for SIN-1.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The vascular endothelium generates a constant flux of NO, achieving concentrations of NO in the artery wall of approximately 100 to 400 nmol/L.48 Even before the identification of EDRF as NO, inactivation by superoxide was inferred from the observation that SOD prolongs the action of EDRF (see Reference 4949 for review). More recent studies have extended these early observations to encompass atherosclerosis, suggesting that the early atherosclerotic lesion shows a poor response to endothelium-derived NO due to increased generation of superoxide.32 33 34 35 36 37 The recent characterization of the product between these two radicals, namely peroxynitrite, has shown that it is a powerful oxidant and could contribute to vascular dysfunction in atherosclerosis.37 38 39 40 41 42 43 44 One of the characteristic reactions of peroxynitrite with proteins is the nitration of tyrosine residues.42 The observation that proteins with nitrated tyrosines are detectable by immunostaining in human atherosclerotic plaques lends strong support to the argument that peroxynitrite is an important oxidant in vivo, although other putative NO-dependent mechanisms leading to tyrosine nitration have been proposed.41 50
Once formed in the vasculature, the fate of peroxynitrite most likely
depends on the immediate environment, particularly the thiol content,
which scavenges and converts at least some of this oxidant to
nitrosothiol.51 Once this protective pathway is
overwhelmed, the prooxidant reactions of peroxynitrite may contribute
to the atherosclerotic process in a number of ways, including the
oxidation of -tocopherol and the conversion of LDL to a
proatherogenic form recognized by the macrophage scavenger
receptor.32 33 34 Despite the presence of potentially
protective pathways, some oxidation of plasma lipids occurs in plasma
even in the presence of lipid-soluble antioxidants.40 This
is in marked contrast to other oxidative processes such as transition
metal-mediated decomposition of lipid peroxides or thermolabile
initiators in which endogenous antioxidants must be
depleted before any significant damage can occur.30
The oxidation of lipids and their subsequent decomposition leads to a
broad array of potential vascular mediators and toxic agents. Of
particular interest are the F2-isoprostanes, a novel class
of prostanoids formed by nonenzymic oxidation of arachidonyl-containing
phospholipids.21 In a recent collaborative study with Frei
and colleagues (Lynch et al29 ), we demonstrated that
esterified F2-isoprostanes were formed after treatment of
plasma and isolated LDL with chemically generated peroxyl radicals
simultaneously with the exhaustion of
endogenous ubiquinol and ascorbate, despite the continued
presence of -tocopherol, urate, ß-carotene, or
lycopene.
This study demonstrates that peroxynitrite or the "peroxynitrite
donor" SIN-1 oxidizes LDL and plasma lipids, with the formation of
F2-isoprostanes. The time course of
F2-isoprostane formation after peroxynitrite exposure and
its inhibition by BHT suggest the initiation of a chain propagating
lipid peroxidation reaction by peroxynitrite. SIN-1 generates both NO
and superoxide simultaneously, with little or no detectable
release of either free radical, consistent with their reaction
together to form peroxynitrite.47 The consequence of this
rapid reaction between the two free radicals is that they are not
available to react with lipids. In any event it has been shown that NO
is an antioxidant and that superoxide is extremely inefficient in
promoting lipid peroxidation.52 53 54 Under these conditions,
therefore, SIN-1 mimics the prolonged exposure of lipids within the
vasculature to a continuous production of NO and superoxide.
Indeed, the characteristics of the product formed from SIN-1
decomposition are essentially identical to peroxynitrite
itself.44 47 For example, peroxynitrite and SIN-1 produce
an oxidant with many of the characteristics of the hydroxyl radical and
is capable of directly oxidizing -tocopherol and
nitrating tyrosine residues on proteins. The addition of SOD converts
this compound from a peroxynitrite donor to an NO donor, with the
relative efficiency of NO generation being dependent on the
concentration of SOD used. For example, the concentration of SOD used
in the present study (100 U/mL) was chosen to avoid adding excess
protein into the experiment, which could scavenge peroxynitrite but
does not completely inhibit the formation of this
oxidant.47 However, in the case of LDL oxidation we have
shown that addition of SOD at only 20 U/mL inhibits oxidation by
approximately 90%,31 and in the present study 100
U/mL resulted in complete inhibition of isoprostane formation by SIN-1
(Fig 4). This and our previous data suggest that small amounts of NO
may protect against lipid peroxidation initiated by peroxynitrite.
Recently, a mechanism for this effect has been elegantly demonstrated
in model systems of lipid oxidation in which the chain-terminating
properties of NO have been identified and the relatively stable
lipid-derived organic nitrates formed as a consequence were
described.53 The continued production of
superoxide and NO under physiological
conditions may contribute to the normal but significant concentrations
of F2-isoprostanes present in the plasma of normal
volunteers.21 22 25
It is of interest to directly compare the effects of peroxynitrite and
SIN-1 in forming F2-isoprostanes. This is, however,
complicated by the difficulty of assessing how much peroxynitrite has
decomposed in solution before encountering an LDL particle. It is
evident that for the same level of protein modification, as assessed by
its increase in electrophoretic mobility, isoprostane formation in LDL
is approximately 3- to 4-fold greater than peroxynitrite when SIN-1 is
used as the prooxidant (on an equimolar basis). In plasma we have no
equivalent mechanism to normalize the dose and exposure of
peroxynitrite and SIN-1, but it is again clear that the
simultaneous generation of NO and
O2- by SIN-1 causes a greater generation of
F2-isoprostanes (approximately 9-fold) than preformed
peroxynitrite (Fig 5). The reasons for this are not clear but could
arise from the fact that during the simultaneous generation
of NO and O2- by SIN-1, some partitioning or
binding of the compound or NO to LDL may occur, resulting in an
increased local concentration of peroxynitrite in or near the lipid
phase of the particle. Similarly, preformed peroxynitrite must
penetrate the phospholipid bilayer and hydrophilic domains of the apo B
protein before it can react with a polyunsaturated fatty acid and
initiate lipid peroxidation. Taken together, these effects may increase
the relative efficiency of SIN-1 in promoting lipid peroxidation when
compared with peroxynitrite. This idea is not without precedent, since
in the studies of hypochlorite as a potential prooxidant of LDL it was
also found that significant modification of the protein could occur
with little or no involvement of lipid.55 Since the
effects of the two treatments are at least different in the extent to
which they may promote lipid peroxidation, it is reasonable to ask
which most realistically models the situation in vivo. At present,
this cannot be answered with certainty, but the most likely site of
formation of peroxynitrite is between inflammatory and adherent cells,
which would result in a mixture of oxidation products derived from
both protein and lipid.
There was considerable variability in the extent of
F2-isoprostane formation by oxidation of LDL within the
individual donors (Table). This individual variability is well
recognized when other markers of lipid peroxidation are examined,
probably reflecting differing endogenous antioxidants and
variable lipid composition. To compare F2-isoprostane
formation in LDL from different donors, we plotted the N-fold increase
in F2-isoprostanes as a function of REM. This is an
independent index of oxidative damage, allowing comparison between the
response of the sample to that of peroxynitrite (Fig 3). These data
suggest that the quantity of F2-isoprostane formed is
correlated with the level of oxidative damage initiated by
peroxynitrite.
The precise mechanism by which peroxynitrite acts as an oxidant is still vigorously disputed and includes direct attack by peroxynitrite or decomposition to form hydroxyl radicals or nitrogen dioxide, either of which could promote lipid peroxidation. However, this uncertainty does not affect the conclusions of this study, since the formation of F2-isoprostanes was peroxynitrite dependent. We are not aware of any equivalent process that could result in the metal-independent formation of F2-isoprostanes in vivo.
The process of peroxynitrite-mediated formation of the
F2-isoprostanes may have
pathophysiological consequences relevant to
atherosclerosis. Some of the
F2-isoprostanes formed (eg,
8-iso-PGF2) inhibit thromboxane-induced
aggregation of platelets and may therefore limit the contribution
of platelets to intimal hyperplasia.29 In addition,
perhaps most importantly, the marked vasoconstrictor effects of some of
the F2-isoprostanes may modulate the vascular responses to
endogenous vasoactive mediators and contribute to the
vascular dysfunction of atherosclerotic vessels.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grant GM-42056 from the National Institutes of Health, Bethesda, Md. Dr Moore is a recipient of an MRC Senior Fellowship.
Received November 15, 1994; accepted May 5, 1995.
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