(Circulation. 2001;103:2277.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Absence of 12/15-Lipoxygenase Expression Decreases Lipid Peroxidation and Atherogenesis in Apolipoprotein E–Deficient Mice
From the Center for Experimental Therapeutics (T.C., D.P., L.Z., G.A.F., C.D.F.) and the Department of Medicine (D.J.R.), University of Pennsylvania, Philadelphia; the Department of Medicine, University of California–San Diego (J.L.W.); and the Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne (J.R.).
Correspondence to Colin D. Funk, Center for Experimental Therapeutics, University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19104-6160. E-mail colin{at}spirit.gcrc.upenn.edu
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Abstract |
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Background—The enzyme 12/15-lipoxygenase (12/15-LO) has been implicated in the oxidative modification of LDL. In a murine model, we tested the hypothesis that deletion of 12/15-LO decreases atherogenesis by reducing oxidant stress, as measured by 2 indices of lipid peroxidation: isoprostane generation and autoantibody formation to malondialdehyde (MDA)-LDL, an epitope of LDL formed as a result of oxidative modification.
Methods and
Results—12/15-LO–deficient
(12/15-LO-/-) mice were crossed with
apolipoprotein E–deficient (apoE-/-)
mice. At 10 weeks of age, atherosclerotic lesion initiation was
significantly delayed in the double-knockout mice. The rate of lesion
progression was diminished at 8 and 12 months, and even at 15 months,
lesion size was reduced 50%
(P<0.0005) compared with
control apoE-/- mice. The urinary and
plasma levels of the specific isoprostane
8,12-iso-iPF2
-VI, as well as IgG
autoantibodies against MDA-LDL, were significantly reduced in the
double-deficient mice in parallel with decreased
atherosclerosis at all time points from 10 weeks to 15
months of age compared with apoE-/-
controls.
Conclusions—Enzymatic action of 12/15-LO contributes significantly to atherosclerotic lesion initiation and propagation in this murine model. Strong positive correlations exist between lesion size, isoprostane levels, and MDA-LDL autoantibodies, providing in vivo evidence for an enzymatic (12/15-LO) component to lipid peroxidation and atherogenesis.
Key Words: atherosclerosis • enzymes • lipoxygenase • lipids
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Atherosclerotic lesions develop in a characteristic fashion, first presenting as fatty streaks, consisting of lipid-rich macrophages (called foam cells) in the intima, beneath an intact endothelial cell layer.1 According to the oxidation hypothesis of atherosclerosis, oxidation of LDL plays a key role in the early pathogenic events, leading to foam-cell formation and the fatty streak.2 3 Products of oxidized LDL (oxLDL) are chemotactic for monocytes, promote endothelial cell binding of monocytes, and once the monocytes have been recruited into the arterial intima, inhibit the motility of macrophages.3 4 5 Macrophages can both initiate the oxidation of LDL and take up oxLDL in an unregulated manner, leading to foam-cell formation. There is now considerable evidence to support the presence of oxLDL in vivo, at least in animal models (reviewed in Reference 33 ). Many enzyme systems or nonenzymatic oxidative mechanisms have been demonstrated to mediate oxidation in vitro.6 The mechanism(s) responsible for oxidation of LDL in vivo, however, remain to be fully defined.
There is now considerable evidence to support a role for 12/15-lipoxygenase (12/15-LO) as important for mediating LDL oxidation and promoting atherogenesis. In vitro, the enzyme can initiate oxidation of LDL,7 and lipoxygenase inhibitors can greatly diminish the ability of macrophages to oxidatively modify LDL.8 When LDL preparations are incubated with 15-LO–transfected fibroblasts, they become seeded with hydroperoxides and develop biological properties of oxLDL, including display of oxidation-specific epitopes recognized by antibodies to oxLDL.9 Rabbit and human atherosclerotic lesions contain 15-LO mRNA/protein,10 stereospecific 15-LO reaction products can be demonstrated in lesions,11 12 and a specific 15-LO inhibitor reduced atherogenesis in rabbits.13 The most convincing data to date come from our recent studies in which disruption of 12/15-LO gene expression greatly diminished atherosclerosis in 15-week-old apolipoprotein E–deficient (apoE-/-) mice.14 Those studies, however, did not look at very early or long-term effects of 12/15-LO deletion on lesion progression, nor were mechanisms explored by which LO deletion retarded atherogenesis.
Here, we examine the impact on atherogenesis of 12/15-LO deletion in apoE-/- mice over various time points up to 15 months of age. To relate these changes to measures of lipid peroxidation, we measured autoantibody titers to malondialdehyde (MDA)-LDL, an epitope of oxLDL generated when LDL undergoes oxidative modification that has previously been shown to be increased in apoE-/- mice15 and to correlate with the extent of atherosclerosis in LDL-receptor-/- mice.16
We also made a more direct measure of in vivo lipid peroxidation. Isoprostanes (iPs), free radical–catalyzed products of arachidonic acid that localize to macrophages and vascular smooth muscle cells in human atherosclerotic plaque, are increased in a variety of syndromes putatively associated with oxidant stress and thus thought to reflect lipid peroxidation in vivo.17 18 19 Antioxidants, such as vitamin E, retard atherogenesis and suppress elevated iP levels,20 and when LDL is oxidized in vitro, iPs are formed in a time-dependent manner.21 22 Given that plasma and urinary iP levels are inversely correlated with aortic lesion area in vitamin E–fed apoE-/- mice20 and that 12/15-LO gene disruption also inhibits atherogenesis in apoE-/- mice,14 we sought to test the hypothesis that 12/15-LO–abolished expression would reduce oxidant stress in apoE-/- mice, as evidenced by decreased lipid peroxidation in parallel with decreased extent of atherosclerosis.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Generation of 12/15-LO-/-/ApoE-/- Double-Knockout Mice
12/15-LO–deficient (12/15-LO-/-) mice were crossbred with apoE-/- mice (backcrossed 7 and 6 times, respectively, to the C57BL/6 background).14 Mice were genotyped either by PCR analysis (apoE) or Southern blot analysis (12/15-LO) as described previously.14 The mice were fed a normal mouse-chow diet (5015; Purina Mills). All animal procedures were carried out in accordance with institutional and NIH guidelines.
Tissue Preparation for Morphometric
Determination of Atherosclerosis
Mice were anesthetized and bled via cardiac
puncture. The aorta and its main branches were dissected from the
aortic valve to the iliac bifurcation, and en face preparations/images
were prepared as
described.14 15
Lipid and Lipoprotein Analysis
Plasma triglyceride and total
cholesterol levels were analyzed as
described.14 Lipoprotein
profiles were determined by fast protein liquid
chromatography gel filtration (Pharmacia LKB
Biotechnology) on 2 Superose 6 columns in
series.23
Determination of Autoantibody Titers Against
OxLDL Epitopes
The titers of IgG autoantibodies against MDA-modified
LDL were determined in individual plasma samples (1:500 dilution) by
sensitive chemiluminescence
detection.24 The amount of
IgG bound to the MDA-LDL antigen was detected with alkaline
phosphatase–labeled anti-mouse IgG. Data are expressed as relative
light units (RLU)/100 ms. All analyses were performed in single
assays, and the intra-assay coefficient of variation was 8% to
10%.
IP Analysis
8,12-iso-iPF2-VI was
measured by stable dilution isotope gas
chromatography/mass spectrometry assay with
[2H4]-8,12-iso-iPF2-VI
internal standard using peak ratios (interassay/intra-assay
variabilities ±4% to
5%25 ). Urine samples were
collected in the presence of 0.1% butylated hydroxytoluene and stored
at -80°C until analysis. An aliquot was stored for
creatinine measurement. Blood samples were obtained via
right ventricular puncture from animals fasted overnight as
previously
described.14
Immunohistochemistry
Immunostaining of aortic root
sections (8 µm) for detection of macrophages was carried out
as described previously.14
Detection of T lymphocytes was performed similarly with goat anti-rat
CD4, CD8 polyclonal antibodies (20 µg/mL; ATCC). Smooth muscle cell
-actin expression was examined by an avidin-biotin–horseradish
peroxidase method (Vector Laboratories) with a primary mouse anti-human
-actin monoclonal antibody conjugated with FITC (Sigma Chemical Co)
and a secondary biotinylated goat anti-FITC antibody
(Sigma).
Statistical Analysis
Initial analyses were performed by Student’s
t test. If the data did not fit
the constraints of this parametric test, data were
analyzed with Kruskal-Wallis ANOVA or the Mann-Whitney
U test. A value of
P<0.05 was considered
significant. Correlations between autoantibody titers, iPs, and extent
of lesions were determined by linear regression analysis with
Instat 2.01 software (Instat Computer Software). Data are
presented as
mean±SEM.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Kinetics of Atherosclerotic Lesion Development in 12/15-LO-/-/ApoE-/-, 12/15-LO+/-/ApoE-/-, and 12/15-LO+/+/ApoE-/- Mice
The present study was designed to explore lesion development throughout the lifespan of 12/15-LO-/- mice bred into apoE-/- mice fed a normal chow diet. Groups of mice with the respective genotypes were euthanized at 10 weeks and 8, 12, and 15 months of age. To investigate any effects of the 12/15-LO gene disruption on atherogenesis independent of the apoE-knockout phenotype, mice deficient in 12/15-LO (12/15-LO-/-/apoE+/+) were euthanized at 8, 15, and 24 months of age.
Total and HDL cholesterol levels were similar
for all animals on the apoE-/-
background at all time points irrespective of their 12/15-LO
genotype
(Table
).
Values of total cholesterol as well as the HDL fractions
were similar to values normally found in
apoE-/- mice on a regular chow diet.
Total and HDL cholesterol levels of the
12/15-LO-/-/apoE+/+
mice were similar to those found in C57BL/6 mice on a normal chow diet.
Triglyceride levels were not significantly different
between apoE-/- mice homozygous
(12/15-LO-/-), heterozygous
(12/15-LO+/-), or wild-type for 12/15-LO
(data not shown). These data indicate that any effects of 12/15-LO
deletion on atherogenesis are independent of changes in plasma
lipoprotein levels.
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By an en face
method,14 the extent of
atherosclerotic surface area was quantified in the aorta
starting directly distal to the aortic valve and ending 
1 cm into
the common iliac arteries. Because lesions commonly develop at
branching points of blood vessels, we included approximately the first
centimeter of major branching arteries, ie, the brachiocephalic trunk,
the left common carotid and subclavian arteries, and the renal
arteries. At 10 weeks, lesions had started to develop in the
12/15-LO+/-/apoE-/-
mice (1263±643 µm2; n=7), and the average
atherosclerotic lesion size in the
12/15-LO+/+/apoE-/-
control mice was 4099±1738 µm2 (n=13;
Figure 1A). Because lesions were observed in only 6 of 13
mice of this genotype at this early time, the SD was high. In
sharp contrast, only one of ten
12/15-LO-/-/apoE-/-
mice had a small detectable atherosclerotic lesion. The observed
differences were statistically significant by nonparametric
testing (P=0.045).
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After 8 months on mouse chow, atherosclerotic lesions
had developed in all mice. The average size of atherosclerotic lesions
in the
12/15-LO-/-/apoE-/-
mice (66 009±5587 µm2; n=12) was
significantly less than that found in
12/15-LO+/-/apoE-/-
mice (95 126±7342 µm2; n=11;
P=0.0044) and
12/15-LO+/+/apoE-/-
mice (90 870±6144 µm2; n=12;
P=0.0067). An absolute
increment in total lesion area occurred in all 3 groups, but the
12/15-LO-/- mice still had the smallest
lesion areas at 1 year of age
(Figure 1B
). The final time point for lesion determination
was 15 months, because apoE-/- mice
usually fail to thrive and often die around this age. Even close to the
end of their natural life span, the average size of atherosclerotic
lesions in the
12/15-LO-/-/apoE-/-
mice (116 203±6756 µm2; n=13) was
significantly less than in
12/15-LO+/-/apoE-/-
mice (258 696±24 374 µm2; n=6;
P=0.0015) and
12/15-LO+/+/apoE-/-
mice (236 249± 19 037 µm2; n=10;
P=0.0005)
(Figure 2). In the absence of
hypercholesterolemia, wild-type C57BL/6 mice
with homozygous 12/15-LO gene disruption
(12/15-LO-/-/apoE+/+)
had no detectable atherosclerotic lesions in their aortas when examined
at 8 months (n=5), 15 months (n=9), or even 2 years of age
(n=6).
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Immunohistochemistry was carried out on aortic root sections
of 8-, 12-, and 15-month-old mice. Although lesions were
consistently smaller in the double-knockout mice, there were no
significant alterations in lesion composition of macrophages
and CD4- or CD8-positive lymphocytes compared with 12/15-LO–expressing
mice, and smooth muscle -actin expression was reduced in a
variable manner at lesion sites in both groups of mice (data not
shown).
Correlation of
8,12-iso-iPF2-VI With Lesion Size in
12/15-LO-/-/ApoE-/-,
12/15-LO+/-/ApoE-/-,
and
12/15-LO+/+/ApoE-/-
Mice
At 10 weeks, urinary
8,12-iso-iPF2-VI was reduced (0.18±0.06
ng/mg creatinine; n=8) in
12/15-LO-/-/apoE-/-
mice compared with
12/15-LO+/-/apoE-/-
mice (0.375±0.025 ng/mg creatinine; n=6) and
12/15-LO+/+/apoE-/-
mice (0.535±0.205 ng/mg creatinine; n=6). This reduction
could be observed at all time points. Plasma
8,12-iso-iPF2-VI was also reduced in the
12/15-LO-/-/apoE-/-
mice compared with
12/15-LO+/-/apoE-/-
and
12/15-LO+/+/apoE-/-
mice. The differences were sustained throughout the study
(Figure 3A). The correlation of urinary or plasma levels of
8,12-iso-iPF2-VI with the extent of lesion
development was highly significant
(r=0.84,
P=0.03 for urinary
8,12-iso-iPF2-VI and
r=0.86,
P=0.009 for plasma
8,12-iso-iPF2-VI;
Figure 3C).
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Correlation of MDA-LDL Autoantibodies With
Lesion Size in
12/15-LO-/-/ApoE-/-,
12/15-LO+/-/ApoE-/-,
and
12/15-LO+/+/ApoE-/-
Mice
Individual plasma samples for MDA-LDL autoantibody
titer measurements were obtained from mice at 10 weeks and 8, 12, and
15 months of age. At 10 weeks, MDA-LDL IgG autoantibody titers were
reduced in
12/15-LO-/-/apoE-/-
mice (2008±607 RLU/100 ms) and
12/15-LO+/-/apoE-/-
mice (2392±361 RLU/100 ms) compared with
12/15-LO+/+/apoE-/-
mice (4453±367 RLU/100 ms). This reduction in MDA-LDL autoantibody
titers could be observed in the homozygous
12/15-LO-/-/apoE-/-
mice at all time points
(Figure 3B).
Titers of MDA-LDL IgG correlated significantly with extent
of atherosclerotic lesion area
(Figure 3D) and with the
8,12-iso-iPF2-VI in plasma and urine
(Figure 4). These correlations were also sustained within
each sex (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There has been substantial indirect evidence to support a role of 12/15-LO in atherogenesis, and we recently provided direct and specific evidence for the involvement of 12/15-LO in this process in vivo.14 The present studies addressed the kinetics of lesion initiation and progression in the 12/15-LO-/-/apoE-/- mouse model. If 12/15-LO were influencing atherogenesis by promoting lipid peroxidation, then one might anticipate a decrement of oxidant stress with deletion of 12/15-LO, which correlates with the decrease in atherogenesis. To examine this hypothesis, we determined the extent of atherosclerotic lesion size and correlated this with 2 distinct proposed markers of oxidant stress, 8,12-iso-iPF2
-VI and MDA-LDL IgG
autoantibodies. In the absence of any significant differences in cholesterol and triglyceride levels, no significant atherosclerotic lesions were observed in 12/15-LO-/-/apoE-/- mice at 10 weeks of age on a normal chow diet, whereas lesion development was already initiated in 12/15-LO+/-/apoE-/- and 12/15-LO+/+/apoE-/- control mice. These observations suggest that although lesion development is eventually initiated in the 12/15-LO-/-/apoE-/- mice, the lesions progress at a slower rate than observed in 12/15-LO+/-/apoE-/- and 12/15-LO+/+/apoE-/- mice. This finding is concordant with data from studies showing that predominantly stereospecific arachidonate and linoleate metabolites are found in early atherosclerotic lesions in humans and rabbits.11 12 Quantification of lesion areas in en face preparations depicts the spread of lesions along the vessel, but not the thickening and maturation of individual lesions. Thus, an increment in lesion surface as quantified via this methodology primarily reflects the development of new lesions. The concept that 12/15-LO is involved in early lesion development is corroborated by our finding that lesion development in 12/15-LO-/- mice is occurring at a slower pace throughout their life span on an apoE-/- background.
Markers that are increased in direct response to oxidative
modification of LDL are likely to reflect local oxidant stress within
the vascular wall. iPs and plasma oxLDL antibodies are such candidates.
iPs are stable prostaglandin isomers that are generated
during oxidative modification of arachidonic acid via a
free radical–catalyzed
mechanism.26 They have
emerged as increasingly promising markers for oxidant stress and lipid
peroxidation in vivo (eg, in
atherosclerosis17 27 28 ).
In addition, antioxidant treatment with vitamin E significantly reduced
iP generation in aortic tissue (as well as in plasma and urine) in
parallel with a reduction in atherosclerotic lesion development in
apoE-/-
mice.20 The present
study also indicates a highly significant correlation of
8,12-iso-iPF2-VI, the most abundant of many
F2-iPs,25
with atherosclerotic lesion stage in
apoE-/- mice and also shows diminished
8,12-iso-iPF2-VI levels in parallel with
decreased atherosclerotic lesion formation in mice lacking 12/15-LO.
This double-knockout model is the first to provide specific evidence
for a crucial role of a lipoxygenase pathway in
atherogenesis, and the data presented in this study strongly
support the hypothesis that decreased oxidant stress is the most likely
cause for diminished lesion development in these animals. Once 12/15-LO
inserts a hydroperoxide in arachidonic or linoleic
acid, it would then render that modified fatty acid more susceptible to
further lipid peroxidation, which by propagation would start a chain
reaction. This, in turn, could lead to the increased generation of
specific iPs. The exact mechanisms linking an enzymatic pathway
(12/15-LO) with nonenzymatic lipid peroxidation and generation of iPs,
however, are unknown at present.
Gene transfer of apoE3 into hypercholesterolemic mice decreases established atherosclerosis, with a concomitant reduction in iPs.29 It is feasible that iPs play a direct role in lesion development in addition to reflecting lesion burden. iPs activate membrane prostanoid receptors and have recently been shown to activate peroxisome proliferator–activated receptors (PPARs),30 31 which in turn could play a major role in atherogenesis through complex and interrelated pathways.32 33 34 Thus, an interesting scenario of 12/15-LO involvement in lipid peroxidation and intracellular signaling is beginning to emerge.
Autoantibodies to epitopes of oxidatively modified LDL are
found in plasma and lesions, with elevated titers of these antibodies
frequently associated with increased vascular disease and antioxidant
treatment of various hypercholesterolemic animal models
reducing lesion progression and antibody titers (reviewed in Reference
33 ). As was the case with 8,12-iso-iPF2-VI, we
found significant correlation between the titers of autoantibodies to
MDA-LDL and atherosclerotic lesion development in the present
study. This finding further strengthens the contention that the
mechanisms by which 12/15-LO mediates atherogenicity is by promoting
lipid peroxidation and the generation of oxLDL.
Because both plasma and urine levels of iP correlate significantly with atherosclerotic lesion development, it seems justified to assume that iP generation is an independent marker for atherogenesis, even though iP generation increases with age.20 In a similar manner, autoantibody titers to MDA-LDL also increase with age even in C57BL/6 mice, although the absolute increase in titers with age is much greater in LDL-receptor-/- hypercholesterolemic mice.35 At present, data to support the oxidation hypothesis in humans are more limited.
In summary, the present study provides in vivo evidence linking 12/15-LO expression and lipid peroxidation to the initiation and propagation of atherosclerotic lesions in apoE-/- mice. It also supports the proposed use of F2-iPs and antibodies against oxLDL epitopes as potentially useful techniques for identifying populations that may have enhanced rates of lipid peroxidation and thus cardiovascular risk.
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Acknowledgments |
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This work was supported by American Heart Association Fellowship F98293E to Dr Cyrus, and in part by NIH grants HL-53558 to Dr Funk, HL-61364 to Dr FitzGerald, DK-44730 to Dr Rokach, and SCOR grant HL-56989 to Dr Witztum.
Received July 27, 2000; revision received December 21, 2000; accepted December 21, 2000.
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  M. H. Nagelin, S. Srinivasan, J. L. Nadler, and C. C. Hedrick Murine 12/15-Lipoxygenase Regulates ATP-binding Cassette Transporter G1 Protein Degradation through p38- and JNK2-dependent Pathways J. Biol. Chem., November 6, 2009; 284(45): 31303 - 31314. [Abstract] [Full Text] [PDF]
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M. Almeida, E. Ambrogini, L. Han, S. C. Manolagas, and R. L. Jilka Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-{gamma} Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton J. Biol. Chem., October 2, 2009; 284(40): 27438 - 27448. [Abstract] [Full Text] [PDF]
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 G. Kronke, J. Katzenbeisser, S. Uderhardt, M. M. Zaiss, C. Scholtysek, G. Schabbauer, A. Zarbock, M. I. Koenders, R. Axmann, J. Zwerina, et al. 12/15-Lipoxygenase Counteracts Inflammation and Tissue Damage in Arthritis J. Immunol., September 1, 2009; 183(5): 3383 - 3389. [Abstract] [Full Text] [PDF]
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 Y. Kayama, T. Minamino, H. Toko, M. Sakamoto, I. Shimizu, H. Takahashi, S. Okada, K. Tateno, J. Moriya, M. Yokoyama, et al. Cardiac 12/15 lipoxygenase-induced inflammation is involved in heart failure J. Exp. Med., July 6, 2009; 206(7): 1565 - 1574. [Abstract] [Full Text] [PDF]
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 S.-H. Choi, R. Harkewicz, J. H. Lee, A. Boullier, F. Almazan, A. C. Li, J. L. Witztum, Y. S. Bae, and Y. I. Miller Lipoprotein Accumulation in Macrophages via Toll-Like Receptor-4-Dependent Fluid Phase Uptake Circ. Res., June 19, 2009; 104(12): 1355 - 1363. [Abstract] [Full Text] [PDF]
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 G. L. Weibel, M. R. Joshi, E. T. Alexander, P. Zhu, I. A. Blair, and G. H. Rothblat Overexpression of Human 15(S)-Lipoxygenase-1 in RAW Macrophages Leads to Increased Cholesterol Mobilization and Reverse Cholesterol Transport Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 837 - 842. [Abstract] [Full Text] [PDF]
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 D. Steinberg The LDL modification hypothesis of atherogenesis: an update J. Lipid Res., April 1, 2009; 50(Supplement): S376 - S381. [Abstract] [Full Text] [PDF]
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 A. J. Merched, K. Ko, K. H. Gotlinger, C. N. Serhan, and L. Chan Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators FASEB J, October 1, 2008; 22(10): 3595 - 3606. [Abstract] [Full Text] [PDF]
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M. H. Nagelin, S. Srinivasan, J. Lee, J. L. Nadler, and C. C. Hedrick 12/15-Lipoxygenase Activity Increases the Degradation of Macrophage ATP-Binding Cassette Transporter G1 Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1811 - 1819. [Abstract] [Full Text] [PDF]
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 B. Ky, A. Burke, S. Tsimikas, M. L. Wolfe, M. G. Tadesse, P. O. Szapary, J. L. Witztum, G. A. FitzGerald, and D. J. Rader The Influence of Pravastatin and Atorvastatin on Markers of Oxidative Stress in Hypercholesterolemic Humans J. Am. Coll. Cardiol., April 29, 2008; 51(17): 1653 - 1662. [Abstract] [Full Text] [PDF]
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R. Harkewicz, K. Hartvigsen, F. Almazan, E. A. Dennis, J. L. Witztum, and Y. I. Miller Cholesteryl Ester Hydroperoxides Are Biologically Active Components of Minimally Oxidized Low Density Lipoprotein J. Biol. Chem., April 18, 2008; 283(16): 10241 - 10251. [Abstract] [Full Text] [PDF]
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D. M. Nikolic, M. C. Gong, J. Turk, and S. R. Post Class A Scavenger Receptor-mediated Macrophage Adhesion Requires Coupling of Calcium-independent Phospholipase A2 and 12/15-Lipoxygenase to Rac and Cdc42 Activation J. Biol. Chem., November 16, 2007; 282(46): 33405 - 33411. [Abstract] [Full Text] [PDF]
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 A. Pirillo, P. Uboldi, G. Pappalardo, H. Kuhn, and A. L. Catapano Modification of HDL3 by mild oxidative stress increases ATP-binding cassette transporter 1-mediated cholesterol efflux Cardiovasc Res, August 1, 2007; 75(3): 566 - 574. [Abstract] [Full Text] [PDF]
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X. Feng, H. Li, A. A. Rumbin, X. Wang, A. La Cava, K. Brechtelsbauer, L. W. Castellani, J. L. Witztum, A. J. Lusis, and B. P. Tsao ApoE-/-Fas-/- C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis, and osteopenia J. Lipid Res., April 1, 2007; 48(4): 794 - 805. [Abstract] [Full Text] [PDF]
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S. Tsimikas, E. S. Brilakis, R. J. Lennon, E. R. Miller, J. L. Witztum, J. P. McConnell, K. S. Kornman, and P. B. Berger Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events J. Lipid Res., February 1, 2007; 48(2): 425 - 433. [Abstract] [Full Text] [PDF]
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J. Huber, A. Furnkranz, V. N. Bochkov, M. K. Patricia, H. Lee, C. C. Hedrick, J. A. Berliner, B. R. Binder, and N. Leitinger Specific monocyte adhesion to endothelial cells induced by oxidized phospholipids involves activation of cPLA2 and lipoxygenase J. Lipid Res., May 1, 2006; 47(5): 1054 - 1062. [Abstract] [Full Text] [PDF]
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A. Boullier, Y. Li, O. Quehenberger, W. Palinski, I. Tabas, J. L. Witztum, and Y. I. Miller Minimally Oxidized LDL Offsets the Apoptotic Effects of Extensively Oxidized LDL and Free Cholesterol in Macrophages Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1169 - 1176. [Abstract] [Full Text] [PDF]
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 C. M. Chinnici, Y. Yao, T. Ding, C. D. Funk, and D. Pratico Absence of 12/15 Lipoxygenase Reduces Brain Oxidative Stress in Apolipoprotein E-Deficient Mice Am. J. Pathol., November 1, 2005; 167(5): 1371 - 1377. [Abstract] [Full Text] [PDF]
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D. T. Bolick, A. W. Orr, A. Whetzel, S. Srinivasan, M. E. Hatley, M. A. Schwartz, and C. C. Hedrick 12/15-Lipoxygenase Regulates Intercellular Adhesion Molecule-1 Expression and Monocyte Adhesion to Endothelium Through Activation of RhoA and Nuclear Factor-{kappa}B Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2301 - 2307. [Abstract] [Full Text] [PDF]
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A. M. Taylor, R. Hanchett, R. Natarajan, C. C. Hedrick, S. Forrest, J. L. Nadler, and C. A. McNamara The Effects of Leukocyte-Type 12/15-Lipoxygenase on Id3-Mediated Vascular Smooth Muscle Cell Growth Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2069 - 2074. [Abstract] [Full Text] [PDF]
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Y. I. Miller, S. Viriyakosol, D. S. Worrall, A. Boullier, S. Butler, and J. L. Witztum Toll-Like Receptor 4-Dependent and -Independent Cytokine Secretion Induced by Minimally Oxidized Low-Density Lipoprotein in Macrophages Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1213 - 1219. [Abstract] [Full Text] [PDF]
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J. Belkner, P. Chaitidis, H. Stender, C. Gerth, R. J. Kuban, T. Yoshimoto, and H. Kuhn Expression of 12/15-Lipoxygenase Attenuates Intracellular Lipid Deposition During In Vitro Foam Cell Formation Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 797 - 802. [Abstract] [Full Text] [PDF]
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J. D. Morrow Quantification of Isoprostanes as Indices of Oxidant Stress and the Risk of Atherosclerosis in Humans Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 279 - 286. [Abstract] [Full Text] [PDF]
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 Y.-S. Kim, Z.-G. Xu, M. A. Reddy, S.-L. Li, L. Lanting, K. Sharma, S. G. Adler, and R. Natarajan Novel Interactions between TGF-{beta}1 Actions and the 12/15-Lipoxygenase Pathway in Mesangial Cells J. Am. Soc. Nephrol., February 1, 2005; 16(2): 352 - 362. [Abstract] [Full Text] [PDF]
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Z. Zhao, M. C. de Beer, L. Cai, R. Asmis, F. C. de Beer, W. J.S. de Villiers, and D. R. van der Westhuyzen Low-Density Lipoprotein From Apolipoprotein E-Deficient Mice Induces Macrophage Lipid Accumulation in a CD36 and Scavenger Receptor Class A-Dependent Manner Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 168 - 173. [Abstract] [Full Text] [PDF]
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 A. Daugherty, D. L. Rateri, H. Lu, T. Inagami, and L. A. Cassis Hypercholesterolemia Stimulates Angiotensin Peptide Synthesis and Contributes to Atherosclerosis Through the AT1A Receptor Circulation, December 21, 2004; 110(25): 3849 - 3857. [Abstract] [Full Text] [PDF]
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P. J. Barter, S. Nicholls, K.-A. Rye, G.M. Anantharamaiah, M. Navab, and A. M. Fogelman Antiinflammatory Properties of HDL Circ. Res., October 15, 2004; 95(8): 764 - 772. [Abstract] [Full Text] [PDF]
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Y. Huo, L. Zhao, M. C. Hyman, P. Shashkin, B. L. Harry, T. Burcin, S. B. Forlow, M. A. Stark, D. F. Smith, S. Clarke, et al. Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, October 5, 2004; 110(14): 2024 - 2031. [Abstract] [Full Text] [PDF]
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 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
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M. Navab, G.M. Anantharamaiah, S. T. Reddy, S. Hama, G. Hough, V. R. Grijalva, A. C. Wagner, J. S. Frank, G. Datta, D. Garber, et al. Oral D-4F Causes Formation of Pre-{beta} High-Density Lipoprotein and Improves High-Density Lipoprotein-Mediated Cholesterol Efflux and Reverse Cholesterol Transport From Macrophages in Apolipoprotein E-Null Mice Circulation, June 29, 2004; 109(25): 3215 - 3220. [Abstract] [Full Text] [PDF]
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M. Navab, G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL J. Lipid Res., June 1, 2004; 45(6): 993 - 1007. [Abstract] [Full Text] [PDF]
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K. S. Meir and E. Leitersdorf Atherosclerosis in the Apolipoprotein E-Deficient Mouse: A Decade of Progress Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1006 - 1014. [Abstract] [Full Text] [PDF]
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D. Pratico, V. Zhukareva, Y. Yao, K. Uryu, C. D. Funk, J. A. Lawson, J. Q. Trojanowski, and V. M.-Y. Lee 12/15-Lipoxygenase Is Increased in Alzheimer's Disease: Possible Involvement in Brain Oxidative Stress Am. J. Pathol., May 1, 2004; 164(5): 1655 - 1662. [Abstract] [Full Text] [PDF]
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 J. H. Dwyer, H. Allayee, K. M. Dwyer, J. Fan, H. Wu, R. Mar, A. J. Lusis, and M. Mehrabian Arachidonate 5-Lipoxygenase Promoter Genotype, Dietary Arachidonic Acid, and Atherosclerosis N. Engl. J. Med., January 1, 2004; 350(1): 29 - 37. [Abstract] [Full Text] [PDF]
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P. A. VanderLaan, C. A. Reardon, and G. S. Getz Site Specificity of Atherosclerosis: Site-Selective Responses to Atherosclerotic Modulators Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 12 - 22. [Abstract] [Full Text] [PDF]
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K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part I: Basic Mechanisms and In Vivo Monitoring of ROS Circulation, October 21, 2003; 108(16): 1912 - 1916. [Full Text] [PDF]
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B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]
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X. Tang, N. Spitzbarth, H. Kuhn, P. Chaitidis, and W. B. Campbell Interleukin-13 Upregulates Vasodilatory 15-Lipoxygenase Eicosanoids in Rabbit Aorta Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1768 - 1774. [Abstract] [Full Text] [PDF]
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 Y. I. Miller, D. S. Worrall, C. D. Funk, J. R. Feramisco, and J. L. Witztum Actin Polymerization in Macrophages in Response to Oxidized LDL and Apoptotic Cells: Role of 12/15-Lipoxygenase and Phosphoinositide 3-Kinase Mol. Biol. Cell, October 1, 2003; 14(10): 4196 - 4206. [Abstract] [Full Text] [PDF]
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 M. A. Reddy, Y.-S. Kim, L. Lanting, and R. Natarajan Reduced Growth Factor Responses in Vascular Smooth Muscle Cells Derived from 12/15-Lipoxygenase-Deficient Mice Hypertension, June 1, 2003; 41(6): 1294 - 1300. [Abstract] [Full Text] [PDF]
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H. Yin, C. M. Havrilla, L. Gao, J. D. Morrow, and N. A. Porter Mechanisms for the Formation of Isoprostane Endoperoxides from Arachidonic Acid. "DIOXETANE" INTERMEDIATE VERSUSbeta -FRAGMENTATION OF PEROXYL RADICALS J. Biol. Chem., May 2, 2003; 278(19): 16720 - 16725. [Abstract] [Full Text] [PDF]
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S. Tsimikas, C. Bergmark, R. W. Beyer, R. Patel, J. Pattison, E. Miller, J. Juliano, and J. L. Witztum Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes J. Am. Coll. Cardiol., February 5, 2003; 41(3): 360 - 370. [Abstract] [Full Text] [PDF]
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 J. D. Morrow and L. J. Roberts The Isoprostanes: Their Role as an Index of Oxidant Stress Status in Human Pulmonary Disease Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): S25 - 30. [Abstract] [Full Text] [PDF]
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L. Fuentes, M. Hernandez, F. J. Fernandez-Aviles, M. S. Crespo, and M. L. Nieto Cooperation Between Secretory Phospholipase A2 and TNF-Receptor Superfamily Signaling: Implications for the Inflammatory Response in Atherogenesis Circ. Res., October 18, 2002; 91(8): 681 - 688. [Abstract] [Full Text] [PDF]
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L. Zhao, C. A. Cuff, E. Moss, U. Wille, T. Cyrus, E. A. Klein, D. Pratico, D. J. Rader, C. A. Hunter, E. Pure, et al. Selective Interleukin-12 Synthesis Defect in 12/15-Lipoxygenase-deficient Macrophages Associated with Reduced Atherosclerosis in a Mouse Model of Familial Hypercholesterolemia J. Biol. Chem., September 13, 2002; 277(38): 35350 - 35356. [Abstract] [Full Text] [PDF]
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X.-C. Jiang, A. R. Tall, S. Qin, M. Lin, M. Schneider, F. Lalanne, V. Deckert, C. Desrumaux, A. Athias, J. L. Witztum, et al. Phospholipid Transfer Protein Deficiency Protects Circulating Lipoproteins from Oxidation Due to the Enhanced Accumulation of Vitamin E J. Biol. Chem., August 23, 2002; 277(35): 31850 - 31856. [Abstract] [Full Text] [PDF]
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K. Hanasaki, K. Yamada, S. Yamamoto, Y. Ishimoto, A. Saiga, T. Ono, M. Ikeda, M. Notoya, S. Kamitani, and H. Arita Potent Modification of Low Density Lipoprotein by Group X Secretory Phospholipase A2 Is Linked to Macrophage Foam Cell Formation J. Biol. Chem., August 2, 2002; 277(32): 29116 - 29124. [Abstract] [Full Text] [PDF]
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D. Steinberg and J. L. Witztum Is the Oxidative Modification Hypothesis Relevant to Human Atherosclerosis?: Do the Antioxidant Trials Conducted to Date Refute the Hypothesis? Circulation, April 30, 2002; 105(17): 2107 - 2111. [Full Text] [PDF]
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M. A. Reddy, P.-R. Thimmalapura, L. Lanting, J. L. Nadler, S. Fatima, and R. Natarajan The Oxidized Lipid and Lipoxygenase Product 12(S)-Hydroxyeicosatetraenoic Acid Induces Hypertrophy and Fibronectin Transcription in Vascular Smooth Muscle Cells via p38 MAPK and cAMP Response Element-binding Protein Activation. MEDIATION OF ANGIOTENSIN II EFFECTS J. Biol. Chem., March 15, 2002; 277(12): 9920 - 9928. [Abstract] [Full Text] [PDF]
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M. E. Rosenfeld Leukocyte Recruitment Into Developing Atherosclerotic Lesions: The Complex Interaction Between Multiple Molecules Keeps Getting More Complex Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 361 - 363. [Full Text] [PDF]
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R. J. Aiello, P.-A. Bourassa, S. Lindsey, W. Weng, A. Freeman, and H. J. Showell Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 443 - 449. [Abstract] [Full Text] [PDF]
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