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Regular Articles |
From the Vascular Medicine and Atherosclerosis Unit,*
Cardiovascular Division, Department of Medicine, Brigham and
Women's Hospital, Harvard Medical School, Boston, Massachusetts; Ares
Serono,
Geneva, Switzerland; and the
Thrombolysis in Myocardial Ischemia Study
Group,
Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,10
enzymes considered crucial for
vulnerable plaque evolution.
Cyclooxygenases convert arachidonic acid
to prostaglandin G/H2 and, hence, regulate
eicosanoid synthesis. Cyclooxygenase-1 (Cox-1), originally purified
from bovine vesicular glands11
and cloned from sheep
vesicular glands,12-14
is constitutively expressed in
many human tissues, eg, stomach, kidney, platelets, and the central
nervous system.15
Interestingly, the prostaglandin
production in these tissues varies and correlates with the degree of
inflammation, despite constitutive prostaglandin G/H synthase
expression. Differential screening eventually revealed the presence of
a second, inducible cyclooxygenase, called prostaglandin endoperoxide
synthase-2 or Cox-2.16,17
Induction of this isoform by
several mediators, including proinflammatory cytokines, such as
interleukin (IL)-1, tumor necrosis factor (TNF), interferon 
,
endotoxin, growth factors, or shear stress implied a function for Cox-2
in both inflammation and regulation of cell growth, as reviewed
elsewhere.18,19
Recent reports further implicate
cyclooxygenase products in the regulation of
angiogenesis20
and of apoptosis.21,22
In vitro, Cox-2 is inducible in fibroblasts23
and mucosal cells,24
as well as in the atheroma-associated
cell types endothelial cells (EC), SMC, and macrophages
(M).25-28
In addition, IL-1 induces Cox-2 in human
saphenous vein and internal mammary arteries segments in organ
culture.29
Even though human atherosclerotic lesions
contain several of the above listed mediators of cyclooxygenase
induction,30
we possess no information concerning the
expression of Cox-1 and/or Cox-2 in atheromatous tissue.
Both cyclooxygenases have a molecular weight of approximately 70 kd, share 70% identity in their amino acid sequence, and possess similar three-dimensional structures.18,31,32 Even though the inducible enzyme Cox-2 closely resembles in structure and catalytic activity the constitutive Cox-1, the two isoforms have important differences in substrate and inhibitor selectivity, their intracellular location, and their biological function.18 Both enzymes use arachidonic acid equally well. Cox-2, however, converts other fatty acid substrates, such as linolenic or linoleic acid, more efficiently. Furthermore, Cox-2 is less sensitive to aspirin inhibition than is Cox-1.33,34 Aspirin inhibits Cox-1 in platelets, reducing thrombotic potential, probably via decreased production of prostaglandins, such as thromboxane A2.35 The variation in the biological function of Cox isoforms may relate to their subcellular localization: Cox-1 primarily in the endoplasmic reticulum and Cox-2 in both the endoplasmic reticulum and the perinuclear space.36
Despite the recognition that the Cox-1 and Cox-2 isoforms have distinct regulation, we have little knowledge of their relative importance in atherogenesis. This issue is particularly important given both the increased recognition of the inflammatory nature of atheroma, which might induce the proinflammatory isoform Cox-2, and the current availability of pharmacological agents that inhibit specifically this isoform. The present study, therefore, tested the hypothesis that human atherosclerotic lesions exhibit augmented Cox-2 expression.
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Human recombinant IL-1ß and TNF
were obtained from Endogen
(Cambridge, MA), Escherichia coli endotoxin
lipopolysaccharide (LPS) from Sigma (St. Louis, MO). Recombinant human
CD 40 ligand (rCD40L) was prepared as described
previously.37
Goat polyclonal antibodies against human
Cox-1 and Cox-2 as well as recombinant human Cox-1 and Cox-2 blocking
peptides were obtained from Santa Cruz Biotechnology (Santa
Cruz, CA). The respective mouse anti-human Cox-1 and Cox-2 monoclonal
antibodies were provided by Cayman Chemicals (Ann Arbor, MI). Control
mAb and rabbit Ig used for immunohistochemistry were obtained from
PharMingen (La Jolla, CA).
Cell Isolation and Culture
Human vascular EC were isolated from saphenous veins by
collagenase treatment (1 mg/ml; Worthington Biochemicals, Freehold, NJ)
and cultured in dishes coated with fibronectin (1.5
µg/cm2
New York Blood Center Reagents, New
York, NY). Cells were maintained in medium 199 (BioWhittaker,
Walkersville, MD), supplemented with 1% penicillin/streptomycin
(BioWhittaker), 5% fetal bovine serum (FBS; Atlanta Biologicals,
Norcross, GA), 50 µg/ml heparin (Sigma) and ECGF (endothelial cell
growth factor; Pel-Freez Biological, Rogers, AK). Human vascular SMC
were isolated from human saphenous veins by explant
outgrowth38
and cultured in DMEM (BioWhittaker)
supplemented with 1% L-glutamine (BioWhittaker), 1%
penicillin/streptomycin, and 10% FBS. Both cell types were subcultured
after trypsinization in 0.5% trypsin (Worthington Biochemicals)/0.2%
EDTA (EM Science, Gibbstown, NJ) in 75-cm2
culture flasks (Becton Dickinson, Franklin Lakes, NJ), and used
throughout passages two to four. Culture media and FBS contained <40
pg endotoxin/ml as determined by the chromogenic Limulus amoebocyte
assay (QLC-1000; BioWhittaker). EC and SMC were characterized by
immunostaining with anti-von Willebrand factor and anti-SMC -actin
antibody (Dako, Carpinteria, CA), respectively. Both cell types were
cultured 24 hours before the experiment in media lacking FBS:
vascular EC were cultured in M199 supplemented with 0.1% human serum
albumin and vascular SMC in insulin/transferrin (IT) medium, as
described previously.39
Mononuclear phagocytes were isolated by density gradient
centrifugation, using Lymphocyte Separation Medium (Organon-Teknika,
Durham, NC), and subsequent counterflow elutriation from freshly
prepared human peripheral blood mononuclear cells (PBMC) obtained from
leukopacs of healthy donors (kindly provided by Dr. B. Rollins, Dana
Farber Cancer Institute, Boston, MA). Mononuclear phagocytes were
either used directly for the experiments (monocytes) or cultured for 1,
3, or 9 days (M) in RPMI 1640 containing 2% human serum (Sigma).
The purity of monocytes and M was 
96%, as determined by
fluorescence-activated cell sorter analysis (anti-human CD68 mAb FITC,
PharMingen). For certain studies, M were stimulated in RPMI 1640
lacking serum.
Immunohistochemistry
Surgical specimens of human carotid atheroma and aorta were
obtained by protocols approved by the Human Investigation Review
Committee at the Brigham and Women's Hospital. Serial cryostat
sections (5 µm) were cut, air dried onto microscope slides (Fisher
Scientific, Pittsburgh, PA), and fixed in acetone at -20°C for 5
minutes. Sections were pre-incubated with phosphate-buffered saline
(PBS) containing 0.3% hydrogen peroxidase activity. The sections were
then incubated for 90 minutes with primary or control (mouse myeloma
protein MOPC-21, Sigma) antibody, diluted in PBS supplemented with 5%
appropriate serum. After washing three times in PBS, sections were
incubated with the respective biotinylated secondary antibody (45
minutes; Vector, Burlingame, CA) followed by avidin-biotin-peroxidase
complex (Vectastain ABC kit, Vector), and antibody binding was
visualized with 3-amino-9-ethyl carbazole (Vector) according to the
recommendations provided by the supplier. For colocalization of Cox-1
or Cox-2 with the respective cell type, double-immunofluorescence
staining was performed. The anti-human Cox-1 and Cox-2 Ab (1:200) was
applied for 90 minutes, followed by biotinylated anti-mouse/goat
secondary antibody for 45 minutes and Texas red-conjugated streptavidin
(Amersham, Arlington Heights, IL). After application of the
avidin/biotin blocking kit (Vector), anti-muscle actin mAb for SMC
(Enzo Diagnostics, New York, NY), anti-CD31 mAb for EC (1:400, Dako),
or anti-CD68 mAb for M (1:600, Dako) were added and sections
incubated overnight at 4°C. Subsequently, biotinylated
horse-anti-mouse secondary antibodies were applied for 30 minutes,
followed by streptavidin-FITC (Amersham).
In Situ Hybridization
In situ hybridization was performed according to the instructions of the manufacturer (Hyb-Probe, Shandon/Lipshaw, Pittsburgh, PA). Briefly, frozen tissue sections obtained as described above were fixed in cold acetone, air-dried, and incubated with a mixture of FITC-labeled Cox-1 (5'-GTGACCTTGTACCGATCGGAAAGAACATCG-3'; 5'-TACGAAGTCGTTCGTCGGGAGGTGAGGTCG3'; 5'-CAACCGAGGTTTGACGAGGGTA GTAAGGAA-3') or random oligomers in hybridization-buffer (30% formamide, 0.6 mol/L NaCl2, 10% dextran sulfate, 50 mmol/L Tris (pH7.5), 0.1% sodium-pyro-phosphate, 0.2% Ficoll, 5 mmol/L EDTA) for 10 minutes at 65°C and subsequently for 2 hours at 37°C in a moist chamber. Finally, slides were washed 3 times and forwarded to the immunological reaction employing alkaline phosphatase-conjugated rabbit Fab' anti-FITC (30 minutes) and Nitroblue tetrazolium/5-bromo-4-chloro-3-indoyl phosphate chromogen solution (1 hour).
Biochemical Analysis of Human Atherosclerotic Lesions
Frozen tissue from five nonatherosclerotic arteries and seven atheromatous carotid plaques were homogenized (IKA-Labortechnik, Dortmund, Germany, Ultra-turrax T 25) and lysed (0.3 mg tissue/ml lysis buffer) as described previously.40 The lysates were clarified (16,000 x g, 15 minutes) and the protein concentration for each tissue extract as well as for the cell culture samples was determined using a bicinchoninic acid protein assay according to the instructions of the manufacturer (Pierce, Rockford, IL).
Western Blot Analysis
Tissue extracts (50 µg total protein/lane), cell extracts (20 µg total protein/lane), and culture supernatants (10x) were separated by standard sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions and blotted to polyvinylidene difluoride membranes (Bio-Rad, Hercules, CA) using a semidry blotting apparatus (0.8 mA/cm2, 30 minutes; Bio-Rad). Blots were blocked and first and second monoclonal antibodies were diluted in 5% defatted dry milk/PBS/0.1% Tween 20. After 1 hour of incubation with the respective primary antibody, blots were washed three times (PBS/0.1% Tween) and the secondary, peroxidase-conjugated goat-anti-mouse antibody (Jackson Immunoresearch, West Grove, PA) was added for another 1 hour. Finally, the blots were washed (20 minutes, PBS/0.1% Tween 20) and immunoreactive proteins were visualized using the Western blot chemiluminescence system (New England Nuclear, Boston, MA).
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Normal arterial tissue (n = 5) and
atherosclerotic lesions (n = 7) contained
immunostainable Cox-1 (Figure 1)
. In
contrast, nonatherosclerotic arterial tissue had little or no Cox-2.
Interestingly, staining for Cox-2 was abundant in atheromatous lesions
compared to normal arterial tissue. Within the lesion, Cox-1 and Cox-2
accumulated in the shoulder region of the lesions as well as the
periphery of the lipid core, areas also staining for M (anti-CD68,
data not shown). Immunofluorescence double-labeling associated the
expression of Cox-1 in normal tissue with vascular EC and SMC (data not
shown). Within the atherosclerotic lesion, both cyclooxygenase isoforms
colocalized with EC and SMC, but showed brightest signals in M
(Figure 2, 3)
. The endothelium of plaque
microvessels also showed prominent Cox-1 and Cox-2 staining (Figure 4)
.
Preincubation of the Cox-antibodies with the respective peptide
inhibited staining, indicating the specificity of the signals obtained
(data not shown). Immunohistochemical analysis performed with the
polyclonal or the monoclonal anti-Cox-1/-2 antibody showed similar
results. Tissues showed no staining with an irrelevant IgG1 antibody
(Figure 1
, bottom left
panel).
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Further characterization of the variation in cell-type specific
expression of Cox-1 in nonatherosclerotic and atheromatous arterial
tissue used in situ hybridization. In accord with the
immunohistochemical data, Cox-1 transcripts localized in EC and SMC of
the normal vessel wall (Figure 5)
. Within human atherosclerotic
lesions, however, Cox-1 mRNA (although expressed in EC and SMC as well)
localized most prominently in the shoulder region of the lesion and the
periphery of the lipid core, areas characterized by
immunohistochemistry on adjacent sections as smooth muscle cell-poor
and M-rich (data not shown). Furthermore, SMC within the tunica
media underlying the lesion as well as in sections with normal vessel
morphology, stained strongly for Cox-1 transcripts. In situ
hybridization with negative control probes yielded no signal.
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Western blot analysis performed on extracts of the surgical
specimens using antibodies identical to those used for the
immunohistochemistry studies revealed immunoreactive Cox-1 in both
normal arterial and atherosclerotic tissue (Figure 6
, right panel). The
analysis demonstrated two major immunoreactive proteins, migrating at
70 kd and 50 kd. The 50-kd band was more pronounced in atherosclerotic
tissue extracts. The higher molecular weight band comigrated with the
prominent immunoreactive protein obtained with lysates of unstimulated
as well as IL-1ß/TNF stimulated EC and SMC. The lower
molecular weight band, however, was particularly prominent in
lysates of M, compared to EC and SMC. Supernatants of either
unstimulated or stimulated EC, SMC or M did not contain Cox-1. In
accord with the immunohistochemical studies, Western blot analysis
revealed no or only little immunoreactive Cox-2 in extracts of
nonatherosclerotic tissue, but showed markedly increased immunoreactive
Cox-2 protein in atheromatous lesions. As in the case of Cox-1, we
observed two immunoreactive Cox-2 proteins with approximate molecular
weights of 70 kd and 50 kd. Also similar to the studies on Cox-1
expression, the higher molecular weight Cox-2 band obtained with tissue
extracts comigrated with the prominent immunoreactive protein detected
in lysates of IL-1ß/TNF-stimulated EC and SMC, whereas the lower
molecular weight form was the prominent band in extracts of activated
M derived from peripheral blood monocytes after nine days of
in vitro culture. Lysates of unstimulated M, but not
of EC or SMC cultures, expressed immunoreactive Cox-2 protein.
Furthermore, IL-1/TNF stimulated EC, but not SMC and M cultures
released immunoreactive Cox-2. Besides IL-1ß/TNF, classic
mediators of Cox-2 expression, we also used rCD40L as a stimulus,
resulting in the increased levels of Cox-2, but not Cox-1, in all three
cell types (Figure 6)
. These findings agree with a recent study
demonstrating that CD40 engagement up-regulates Cox-2 in human lung
fibroblasts.23
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,
we analyzed whether M differentiation might regulate expression
of the observed immunoreactive bands. Freshly isolated peripheral
blood monocytes as well as M derived from monocytes after 1 day of
in vitro culture, incubated for 24 hours with medium or LPS,
expressed Cox-1 constitutively with a molecular weight of 70 kd (Figure 7)
. After 3 and, more markedly, after 9 days of in vitro
culture, a constitutively expressed second immunoreactive Cox-1 and
Cox-2 protein was detected with an molecular weight of approximately 50
kd. Western blot analysis on these lysates for Cox-2 revealed that the
inducibility of the 70-kd form diminishes with increased time in
culture of the M. In contrast, the lower molecular weight form, only
moderately expressed in freshly isolated or 1-day cultured
monocyte-derived M, rose with time of culture. Stimulation of M
with rCD40L yielded findings similar to those described above for
LPS-stimulated cultures (data not shown).
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of the shoulder region and the lipid core
periphery, not SMC, contain most of the Cox-1 protein within the
lesion. In contrast, medial SMC underlying the plaque as well as those
in adjacent sections with normal morphology exhibit prominent Cox-1
staining. This finding may have functional importance, because
different cell types can regulate the production of different
eicosanoids. Endothelium predominantly releases prostaglandin
I2,42
a potent inhibitor of platelet
activation and cholesterol accumulation,5,6,43
whereas
M, not present in normal arterial tissue, produce an array of
prostanoids, including prostaglandin E2 and
thromboxane A2,28
considered the
more atherogenic eicosanoids. The in vivo finding that
prostacyclin agonists suppress M atherogenic activity and thus
inhibit the development of early atherosclerosis44
heightens the relevance of M-derived eicosanoids. Interestingly,
previous studies demonstrated that cyclooxygenase products, such as
PGI2, but not PGE2, augment
cholesteryl ester hydrolase activity, whereas
PGE2, but not PGI2,
inhibits Acyl-CoA cholesterol acyl-transferase activity in human
vascular SMC,45,46
highlighting a possible lipid
accumulation-reducing (hence anti-atherogenic) function of elevated
Cox-2 expression. Future studies are needed to determine whether and
how enhanced cyclooxygenase expression functionally affects
atherogenesis and the net effect in vivo of the interplay
between the anti- and pro-atherogenic products of cyclooxygenases,
particularly with regard to the vascular wall-associated,
Cox-2-mediated synthesis of prostacyclin, a potent vasodilator and
endogenous inhibitor of platelet aggregation.47 The constitutive expression of Cox-1 in diseased as well as undiseased arterial tissue, however, implicates a more physiological rather than inflammatory role of this enzyme with homeostatic functions, as recently reviewed elsewhere.48
Interestingly, both Cox-1 and Cox-2 predominantly localize with
lesional M, a finding that agrees with observations in abdominal
aortic aneurysms, where M also represent the majority of
Cox-expressing cells.49
Increased Cox-2 expression within
the lesion, a site of chronic inflammation, further agrees with reports
describing Cox-2 expression in atheroma-associated cells, including EC,
SMC, and M,25-28
on stimulation with proinflammatory
cytokines such as IL-1 and TNF, mediators found within human
atherosclerotic lesions.30
We recently demonstrated
the presence of another inflammatory pathway in the atherosclerotic
plaque, the CD40-CD40L receptor-ligand pair,50
which
modulates atheroma-associated functions in
vitro39,50-52
and in vivo.53
We therefore tested whether CD40 ligation affects the expression of
either cyclooxygenase in vascular cells. Our finding that recombinant
CD40L potently stimulates the expression of cyclooxygenase-2 in EC,
SMC, and M agrees with the recently published study of Zhang et
al,23
demonstrating that CD40 engagement up-regulates this
isoform in human lung fibroblasts. The colocalization of the enzyme
with CD40-positive lesional EC, SMC, and M (GK Sukhova, U
Schönbeck, unpublished observations) supports the potential
importance of CD40/CD40L in the regulation of Cox-2 within human
atheroma.
Some eicosanoids may play a protective role in cardiovascular and inflammatory diseases, as they reduce adhesion molecule expression, platelet activation, and SMC proliferation.5-7,43,54 In contrast, studies with Cox inhibitors indicated a proinflammatory effect of Cox-2.55,56 An intriguing and novel potential proatherogenic mechanism of cyclooxygenase products is supported by the very recent demonstration by Tsujii et al20 that Cox-1 activity in EC modulates angiogenesis. Neovessel formation, furthermore, required the presence of Cox-2, mediating the synthesis of angiogenic factors. The formation of neovessels may contribute to the evolution of the plaque.57 Indeed, the microvascular endothelium prominently expressed both Cox isoforms, raising the possibility that parallel presence of Cox-1 and Cox-2 within the lesion contributes to the formation of new blood vessels, thus allowing the plaque to expand.
Prostanoids also have potent actions on vascular SMC, regulating
contractility, cholesterol metabolism, and
proliferation.5-7
Increased expression of cyclooxygenases
might thus contribute to the accumulation of lipids in lesional SMC
(and M), favoring formation of SMC- and M-derived foam cells
within atheroma. On the other hand, antiproliferative and
antimigratory58
actions of Cox products on human vascular
SMC, in combination with our finding that the expression of lesional
cyclooxygenases depends mainly on the content of M, suggests
potential contributions of the enzymes to the evolution of a lesion
toward an SMC-depleted and M-enriched, and thus more vulnerable,
plaque. Interestingly, prostaglandin E2, a
predominant eicosanoid of M, induces,10
whereas
PGI2, the predominant arachidonic acid product in
vascular cells, inhibits58
the expression of MMPs, enzymes
considered crucial in the degradation of plaque stability. Our previous
description40
of various MMPs in regions reported here as
Cox-positive and found to be M-enriched suggest that such regulation
of MMP expression by Cox products may operate in vivo.
Furthermore, we found by Western blot analysis that morphologically
stable (SMC-enriched and M-depleted) plaques expressed substantially
less Cox-1, Cox-2, and MMPs compared to lesions with more unstable
features (U Schönbeck, GK Sukhova, unpublished observation).
Finally, prostaglandins inhibit the production of extracellular matrix
macromolecules, such as fibronectin and type I and III collagen,
further favoring plaque fragility.59
It remains to be determined how cyclooxygenase products mediate their
actions. Two classes of prostaglandin receptors can transduce signals
on binding of the ligand: the G-coupled cytoplasmic
receptors60
and the nuclear peroxisome
proliferator-activated receptor (PPAR) class.61
The two
Cox isoforms may exert different functions18
because of
their location in separate subcellular compartments.36
As
Cox-2, but not Cox-1,36
localizes in the perinuclear
region, its product may have more ready access to nuclear receptors.
One Cox product, prostaglandin J2, is a potent
ligand for the PPAR-,61,62
a nuclear receptor that
forms parts of a transcriptional complex after ligand
binding.63
We and others have previously demonstrated that
atheroma-associated cells express PPARs, that ligation by prostaglandin
J2 regulates atheroma-associated gene
expression within these cells, and that PPARs are expressed within
human atherosclerotic lesions.58,61,62,64
In summary, this study demonstrates the expression of both Cox-1
and Cox-2 by EC, SMC, and particularly by M within human
atherosclerotic lesions. Although the in vivo function of
the two isoforms remains to be determined, atherogenic rather than
anti-atherogenic effects may prevail. The present findings indicate new
potential inflammatory pathways in the evolution of atherosclerotic
lesions, which have therapeutic implications in view of the recent
availability of selective Cox-1 and particularly Cox-2 inhibitors.
Conclusions from our findings on the potential role of Cox-2 inhibitors
can only be speculative in nature. However, these findings suggest, in
combination with previous reports that selective inhibition of Cox-2
results in profound suppression of
PGE265
andsystemic prostacyclin
biosynthesis,66
mediators mostly considered
anti-atherogenic, that future clinical trials may have to consider the
possibility of proatherogenic effects during treatment with
Cox-2-specific inhibitors.
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Supported in part by grants of the National Heart, Lung and Blood Institute to Dr. Peter Libby (HL-56985) and performed during the tenure of the Paul Dudley White fellowship of the American Heart Association by Dr. Uwe Schönbeck.
Accepted for publication June 29, 1999.
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I. G. E. Zarraga and E. R. Schwarz Coxibs and Heart Disease: What We Have Learned and What Else We Need to Know J. Am. Coll. Cardiol., January 2, 2007; 49(1): 1 - 14. [Abstract] [Full Text] [PDF]
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 V. N. Bochkov, M. Philippova, O. Oskolkova, A. Kadl, A. Furnkranz, E. Karabeg, T. Afonyushkin, F. Gruber, J. Breuss, A. Minchenko, et al. Oxidized Phospholipids Stimulate Angiogenesis Via Autocrine Mechanisms, Implicating a Novel Role for Lipid Oxidation in the Evolution of Atherosclerotic Lesions Circ. Res., October 13, 2006; 99(8): 900 - 908. [Abstract] [Full Text] [PDF]
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 M. Massaro, A. Habib, L. Lubrano, S. D. Turco, G. Lazzerini, T. Bourcier, B. B. Weksler, and R. De Caterina The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC{varepsilon} inhibition PNAS, October 10, 2006; 103(41): 15184 - 15189. [Abstract] [Full Text] [PDF]
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T. Raj, P. Kanellakis, G. Pomilio, G. Jennings, A. Bobik, and A. Agrotis Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1845 - 1851. [Abstract] [Full Text] [PDF]
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W.-G. Deng, S.-T. Tang, H.-P. Tseng, and K. K. Wu Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding Blood, July 15, 2006; 108(2): 518 - 524. [Abstract] [Full Text] [PDF]
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 H. E Vonkeman, J. R B J Brouwers, and M. A F J van de Laar Understanding the NSAID related risk of vascular events. BMJ, April 15, 2006; 332(7546): 895 - 898. [Full Text] [PDF]
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 N. Dronadula, F. Rizvi, E. Blaskova, Q. Li, and G. N. Rao Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility J. Lipid Res., April 1, 2006; 47(4): 767 - 777. [Abstract] [Full Text] [PDF]
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 P.-S. Wong, A. Asmat, Y.-H. Chan, and C.-N. Lee A randomized, double-blind, placebo-controlled trial of a COX-2 inhibitor (Rofecoxib) in patients undergoing coronary artery bypass surgery Interactive CardioVascular and Thoracic Surgery, April 1, 2006; 5(2): 101 - 104. [Abstract] [Full Text] [PDF]
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 R. C. Harris and M. D. Breyer Update on Cyclooxygenase-2 Inhibitors Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 236 - 245. [Abstract] [Full Text] [PDF]
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S. Pavlovic, B. Du, K. Sakamoto, K. M. F. Khan, C. Natarajan, R. M. Breyer, A. J. Dannenberg, and D. J. Falcone Targeting Prostaglandin E2 Receptors as an Alternative Strategy to Block Cyclooxygenase-2-dependent Extracellular Matrix-induced Matrix Metalloproteinase-9 Expression by Macrophages J. Biol. Chem., February 10, 2006; 281(6): 3321 - 3328. [Abstract] [Full Text] [PDF]
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 V. R. Babaev, L. Ding, J. Reese, J. D. Morrow, M. D. Breyer, S. K. Dey, S. Fazio, and M. F. Linton Cyclooxygenase-1 Deficiency in Bone Marrow Cells Increases Early Atherosclerosis in Apolipoprotein E- and Low-Density Lipoprotein Receptor-Null Mice Circulation, January 3, 2006; 113(1): 108 - 117. [Abstract] [Full Text] [PDF]
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 R. S. Deeb, H. Shen, C. Gamss, T. Gavrilova, B. D. Summers, R. Kraemer, G. Hao, S. S. Gross, M. Laine, N. Maeda, et al. Inducible Nitric Oxide Synthase Mediates Prostaglandin H2 Synthase Nitration and Suppresses Eicosanoid Production Am. J. Pathol., January 1, 2006; 168(1): 349 - 362. [Abstract] [Full Text] [PDF]
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 S.-p. Zhao, P. Deng, H.-g. Huang, Z.-m. Xu, H.-y. Dai, S.-c. Hong, J. Yang, and H.-n. Zhou Expression of COX-2 mRNA in Peripheral Blood Monocytes from Patients with Acute Myocardial Infarction and Its Significance Clin. Chem., November 1, 2005; 51(11): 2170 - 2173. [Full Text] [PDF]
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 Y. Lu and L. M. Wahl Oxidative Stress Augments the Production of Matrix Metalloproteinase-1, Cyclooxygenase-2, and Prostaglandin E2 through Enhancement of NF-{kappa}B Activity in Lipopolysaccharide-Activated Human Primary Monocytes J. Immunol., October 15, 2005; 175(8): 5423 - 5429. [Abstract] [Full Text] [PDF]
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 S. A.H. Zaidi Coxibs and cardiovascular risk Can. Med. Assoc. J., October 11, 2005; 173(8): 852 - 853. [Full Text] [PDF]
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 E. Fosslien Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs Ann. Clin. Lab. Sci., October 1, 2005; 35(4): 347 - 385. [Abstract] [Full Text] [PDF]
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I. E. Hoefer, S. Grundmann, S. Schirmer, N. van Royen, B. Meder, C. Bode, J. J. Piek, and I. R. Buschmann Aspirin, But Not Clopidogrel, Reduces Collateral Conductance in a Rabbit Model of Femoral Artery Occlusion J. Am. Coll. Cardiol., September 20, 2005; 46(6): 994 - 1001. [Abstract] [Full Text] [PDF]
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B. F. McAdam, D. Byrne, J. D. Morrow, and J. A. Oates Contribution of Cyclooxygenase-2 to Elevated Biosynthesis of Thromboxane A2 and Prostacyclin in Cigarette Smokers Circulation, August 16, 2005; 112(7): 1024 - 1029. [Abstract] [Full Text] [PDF]
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E. M. Antman, D. DeMets, and J. Loscalzo Cyclooxygenase Inhibition and Cardiovascular Risk Circulation, August 2, 2005; 112(5): 759 - 770. [Full Text] [PDF]
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 B. Rigas and K. Kashfi Cancer Prevention: A New Era beyond Cyclooxygenase-2 J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 1 - 8. [Abstract] [Full Text] [PDF]
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J. Steffel, M. Hermann, H. Greutert, S. Gay, T. F. Luscher, F. Ruschitzka, and F. C. Tanner Celecoxib Decreases Endothelial Tissue Factor Expression Through Inhibition of c-Jun Terminal NH2 Kinase Phosphorylation Circulation, April 5, 2005; 111(13): 1685 - 1689. [Abstract] [Full Text] [PDF]
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K. K. Wu, J.-Y. Liou, and K. Cieslik Transcriptional Control of COX-2 via C/EBP{beta} Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 679 - 685. [Abstract] [Full Text] [PDF]
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 T. A. Babcock, T. Dekoj, and N. J. Espat Experimental Studies Defining {omega}-3 Fatty Acid Antiinflammatory Mechanisms and Abrogation of Tumor-Related Syndromes Nutr Clin Pract, February 1, 2005; 20(1): 62 - 74. [Abstract] [Full Text] [PDF]
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T. Watanabe, T. A. Barker, and B. C. Berk Angiotensin II and the Endothelium: Diverse Signals and Effects Hypertension, February 1, 2005; 45(2): 163 - 169. [Abstract] [Full Text] [PDF]
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K. M. Egan, M. Wang, M. B. Lucitt, A. M. Zukas, E. Pure, J. A. Lawson, and G. A. FitzGerald Cyclooxygenases, Thromboxane, and Atherosclerosis: Plaque Destabilization by Cyclooxygenase-2 Inhibition Combined With Thromboxane Receptor Antagonism Circulation, January 25, 2005; 111(3): 334 - 342. [Abstract] [Full Text] [PDF]
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 O. Beloqui, J. A. Paramo, J. Orbe, A. Benito, I. Colina, A. Monasterio, and J. Diez Monocyte cyclooxygenase-2 overactivity: a new marker of subclinical atherosclerosis in asymptomatic subjects with cardiovascular risk factors? Eur. Heart J., January 2, 2005; 26(2): 153 - 158. [Abstract] [Full Text] [PDF]
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D. X. Zhang, K. M. Gauthier, Y. Chawengsub, B. B. Holmes, and W. B. Campbell Cyclooxygenase- and lipoxygenase-dependent relaxation to arachidonic acid in rabbit small mesenteric arteries Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H302 - H309. [Abstract] [Full Text] [PDF]
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T. Kumagai, N. Matsukawa, Y. Kaneko, Y. Kusumi, M. Mitsumata, and K. Uchida A Lipid Peroxidation-derived Inflammatory Mediator: IDENTIFICATION OF 4-HYDROXY-2-NONENAL AS A POTENTIAL INDUCER OF CYCLOOXYGENASE-2 IN MACROPHAGES J. Biol. Chem., November 12, 2004; 279(46): 48389 - 48396. [Abstract] [Full Text] [PDF]
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 D. L. Simmons, R. M. Botting, and T. Hla Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition Pharmacol. Rev., September 1, 2004; 56(3): 387 - 437. [Abstract] [Full Text] [PDF]
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R. Natarajan and J. L. Nadler Lipid Inflammatory Mediators in Diabetic Vascular Disease Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1542 - 1548. [Abstract] [Full Text] [PDF]
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 Q. Cai, L. Lanting, and R. Natarajan Growth factors induce monocyte binding to vascular smooth muscle cells: implications for monocyte retention in atherosclerosis Am J Physiol Cell Physiol, September 1, 2004; 287(3): C707 - C714. [Abstract] [Full Text] [PDF]
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P. Bogaty, J. M. Brophy, M. Noel, L. Boyer, S. Simard, F. Bertrand, and G. R. Dagenais Impact of Prolonged Cyclooxygenase-2 Inhibition on Inflammatory Markers and Endothelial Function in Patients With Ischemic Heart Disease and Raised C-Reactive Protein: A Randomized Placebo-Controlled Study Circulation, August 24, 2004; 110(8): 934 - 939. [Abstract] [Full Text] [PDF]
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K. S. Michelsen, M. H. Wong, P. K. Shah, W. Zhang, J. Yano, T. M. Doherty, S. Akira, T. B. Rajavashisth, and M. Arditi Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E PNAS, July 20, 2004; 101(29): 10679 - 10684. [Abstract] [Full Text] [PDF]
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R. K. Upmacis, R. S. Deeb, M. J. Resnick, R. Lindenbaum, C. Gamss, D. Mittar, and D. P. Hajjar Involvement of the mitogen-activated protein kinase cascade in peroxynitrite-mediated arachidonic acid release in vascular smooth muscle cells Am J Physiol Cell Physiol, June 1, 2004; 286(6): C1271 - C1280. [Abstract] [Full Text] [PDF]
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K. M. F. Khan, L. R. Howe, and D. J. Falcone Extracellular Matrix-induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression J. Biol. Chem., May 21, 2004; 279(21): 22039 - 22046. [Abstract] [Full Text] [PDF]
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M. Sussmann, M. Sarbia, J. Meyer-Kirchrath, R.M. Nusing, K. Schror, and J.W. Fischer Induction of Hyaluronic Acid Synthase 2 (HAS2) in Human Vascular Smooth Muscle Cells by Vasodilatory Prostaglandins Circ. Res., March 19, 2004; 94(5): 592 - 600. [Abstract] [Full Text] [PDF]
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 W. Dai and R. A. Kloner Relationship Between Cyclooxygenase-2 Inhibition and Thrombogenesis Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1): 51 - 59. [Abstract] [PDF]
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 N. Shanmugam, I. T. Gaw Gonzalo, and R. Natarajan Molecular Mechanisms of High Glucose-Induced Cyclooxygenase-2 Expression in Monocytes Diabetes, March 1, 2004; 53(3): 795 - 802. [Abstract] [Full Text] [PDF]
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 S. de Pascual-Teresa, K. L. Johnston, M. S. DuPont, K. A. O'Leary, P. W. Needs, L. M. Morgan, M. N. Clifford, Y. Bao, and G. Williamson Quercetin Metabolites Downregulate Cyclooxygenase-2 Transcription in Human Lymphocytes Ex Vivo but Not In Vivo J. Nutr., March 1, 2004; 134(3): 552 - 557. [Abstract] [Full Text] [PDF]
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W. H. Frishman Cyclooxygenase inhibition in patients with coronary artery disease J. Am. Coll. Cardiol., February 18, 2004; 43(4): 532 - 533. [Full Text] [PDF]
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F. Cipollone, B. Rocca, and C. Patrono Cyclooxygenase-2 Expression and Inhibition in Atherothrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 246 - 255. [Abstract] [Full Text]
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O. A. Belton, A. Duffy, S. Toomey, and D. J. Fitzgerald Cyclooxygenase Isoforms and Platelet Vessel Wall Interactions in the Apolipoprotein E Knockout Mouse Model of Atherosclerosis Circulation, December 16, 2003; 108(24): 3017 - 3023. [Abstract] [Full Text] [PDF]
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L. M. Title, K. Giddens, M. M. McInerney, M. J. McQueen, and B. A. Nassar Effect of cyclooxygenase-2 inhibition with rofecoxib on endothelial dysfunction and inflammatory markers in patients with coronary artery disease J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1747 - 1753. [Abstract] [Full Text] [PDF]
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S. Verma and P. E. Szmitko Coxibs and the endothelium J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1754 - 1756. [Full Text] [PDF]
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M. Hermann, G. Camici, A. Fratton, D. Hurlimann, F. C. Tanner, J. P. Hellermann, M. Fiedler, J. Thiery, M. Neidhart, R. E. Gay, et al. Differential Effects of Selective Cyclooxygenase-2 Inhibitors on Endothelial Function in Salt-Induced Hypertension Circulation, November 11, 2003; 108(19): 2308 - 2311. [Abstract] [Full Text] [PDF]
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 G. J. Hankey and J. W. Eikelboom Cyclooxygenase-2 Inhibitors: Are They Really Atherothrombotic, and If Not, Why Not? Stroke, November 1, 2003; 34(11): 2736 - 2740. [Abstract] [Full Text] [PDF]
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S. S. Barbieri, S. Eligini, M. Brambilla, E. Tremoli, and S. Colli Reactive oxygen species mediate cyclooxygenase-2 induction during monocyte to macrophage differentiation: critical role of NADPH oxidase Cardiovasc Res, October 15, 2003; 60(1): 187 - 197. [Abstract] [Full Text] [PDF]
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F. Bea, E. Blessing, B. J Bennett, C. C. Kuo, L. A. Campbell, J. Kreuzer, and M. E Rosenfeld Chronic inhibition of cyclooxygenase-2 does not alter plaque composition in a mouse model of advanced unstable atherosclerosis Cardiovasc Res, October 15, 2003; 60(1): 198 - 204. [Abstract] [Full Text] [PDF]
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N. Shanmugam, Y. S. Kim, L. Lanting, and R. Natarajan Regulation of Cyclooxygenase-2 Expression in Monocytes by Ligation of the Receptor for Advanced Glycation End Products J. Biol. Chem., September 12, 2003; 278(37): 34834 - 34844. [Abstract] [Full Text] [PDF]
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E. F. de Assis, A. R. Silva, L. F. C. Caiado, G. K. Marathe, G. A. Zimmerman, S. M. Prescott, T. M. McIntyre, P. T. Bozza, and H. C. de Castro-Faria-Neto Synergism Between Platelet-Activating Factor-Like Phospholipids and Peroxisome Proliferator-Activated Receptor {gamma} Agonists Generated During Low Density Lipoprotein Oxidation That Induces Lipid Body Formation in Leukocytes J. Immunol., August 15, 2003; 171(4): 2090 - 2098. [Abstract] [Full Text] [PDF]
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O. Belton and D. Fitzgerald Cyclooxygenase-2 inhibitors and atherosclerosis J. Am. Coll. Cardiol., May 21, 2003; 41(10): 1820 - 1822. [Full Text] [PDF]
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S. Bousserouel, A. Brouillet, G. Bereziat, M. Raymondjean, and M. Andreani Different effects of n-6 and n-3 polyunsaturated fatty acids on the activation of rat smooth muscle cells by interleukin-1{beta} J. Lipid Res., March 1, 2003; 44(3): 601 - 611. [Abstract] [Full Text] [PDF]
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R. Chenevard, D. Hurlimann, M. Bechir, F. Enseleit, L. Spieker, M. Hermann, W. Riesen, S. Gay, R. E. Gay, M. Neidhart, et al. Selective COX-2 Inhibition Improves Endothelial Function in Coronary Artery Disease Circulation, January 28, 2003; 107(3): 405 - 409. [Abstract] [Full Text] [PDF]
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K. Takayama, G. Garcia-Cardena, G. K. Sukhova, J. Comander, M. A. Gimbrone Jr., and P. Libby Prostaglandin E2 Suppresses Chemokine Production in Human Macrophages through the EP4 Receptor J. Biol. Chem., November 8, 2002; 277(46): 44147 - 44154. [Abstract] [Full Text] [PDF]
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R. S. Deeb, M. J. Resnick, D. Mittar, T. McCaffrey, D. P. Hajjar, and R. K. Upmacis Tyrosine nitration in prostaglandin H2 synthase J. Lipid Res., October 1, 2002; 43(10): 1718 - 1726. [Abstract] [Full Text] [PDF]
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H. Inoue, Y. Taba, Y. Miwa, C. Yokota, M. Miyagi, and T. Sasaguri Transcriptional and Posttranscriptional Regulation of Cyclooxygenase-2 Expression by Fluid Shear Stress in Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., September 1, 2002; 22(9): 1415 - 1420. [Abstract] [Full Text] [PDF]
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D. Bishop-Bailey, T. Hla, and T. D. Warner Intimal Smooth Muscle Cells as a Target for Peroxisome Proliferator-Activated Receptor-{gamma} Ligand Therapy Circ. Res., August 9, 2002; 91(3): 210 - 217. [Abstract] [Full Text] [PDF]
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B. Pitt, C. Pepine, and J. T. Willerson Cyclooxygenase-2 Inhibition and Cardiovascular Events Circulation, July 9, 2002; 106(2): 167 - 169. [Full Text] [PDF]
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 J. A. Ardans, A. P. Economou, J. M. Martinson Jr., M. Zhou, and L. M. Wahl Oxidized low-density and high-density lipoproteins regulate the production of matrix metalloproteinase-1 and -9 by activated monocytes J. Leukoc. Biol., June 1, 2002; 71(6): 1012 - 1018. [Abstract] [Full Text] [PDF]
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C. Kramer, J. Sunkomat, J. Witte, M. Luchtefeld, M. Walden, B. Schmidt, R. H. Boger, W.-G. Forssmann, H. Drexler, and B. Schieffer Angiotensin II Receptor-Independent Antiinflammatory and Antiaggregatory Properties of Losartan: Role of the Active Metabolite EXP3179 Circ. Res., April 19, 2002; 90(7): 770 - 776. [Abstract] [Full Text] [PDF]
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A. V. Pontsler, A. St. Hilaire, G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre Cyclooxygenase-2 Is Induced in Monocytes by Peroxisome Proliferator Activated Receptor gamma and Oxidized Alkyl Phospholipids from Oxidized Low Density Lipoprotein J. Biol. Chem., April 5, 2002; 277(15): 13029 - 13036. [Abstract] [Full Text] [PDF]
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E. Connolly, D. J. Bouchier-Hayes, E. Kaye, A. Leahy, D. Fitzgerald, and O. Belton Cyclooxygenase Isozyme Expression and Intimal Hyperplasia in a Rat Model of Balloon Angioplasty J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 393 - 398. [Abstract] [Full Text] [PDF]
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M. Yamada, Y. Numaguchi, K. Okumura, M. Harada, K. Naruse, H. Matsui, T. Ito, and T. Hayakawa Prostacyclin Synthase Gene Transfer Modulates Cyclooxygenase-2-Derived Prostanoid Synthesis and Inhibits Neointimal Formation in Rat Balloon-Injured Arteries Arterioscler. Thromb. Vasc. Biol., February 1, 2002; 22(2): 256 - 262. [Abstract] [Full Text] [PDF]
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U. Schonbeck and P. Libby CD40 Signaling and Plaque Instability Circ. Res., December 7, 2001; 89(12): 1092 - 1103. [Abstract] [Full Text] [PDF]
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S. T. Davidge Prostaglandin H Synthase and Vascular Function Circ. Res., October 12, 2001; 89(8): 650 - 660. [Abstract] [Full Text] [PDF]
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G. E. Caughey, L. G. Cleland, P. S. Penglis, J. R. Gamble, and M. J. James Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective Up-Regulation of Prostacyclin Synthesis by COX-2 J. Immunol., September 1, 2001; 167(5): 2831 - 2838. [Abstract] [Full Text] [PDF]
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F. Cipollone, C. Prontera, B. Pini, M. Marini, M. Fazia, D. De Cesare, A. Iezzi, S. Ucchino, G. Boccoli, V. Saba, et al. Overexpression of Functionally Coupled Cyclooxygenase-2 and Prostaglandin E Synthase in Symptomatic Atherosclerotic Plaques as a Basis of Prostaglandin E2-Dependent Plaque Instability Circulation, August 21, 2001; 104(8): 921 - 927. [Abstract] [Full Text] [PDF]
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J. K. Hennan, J. Huang, T. D. Barrett, E. M. Driscoll, D. E. Willens, A. M. Park, L. J. Crofford, and B. R. Lucchesi Effects of Selective Cyclooxygenase-2 Inhibition on Vascular Responses and Thrombosis in Canine Coronary Arteries Circulation, August 14, 2001; 104(7): 820 - 825. [Abstract] [Full Text] [PDF]
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 I. A. Mardini and G. A. FitzGerald Selective Inhibitors of Cyclooxygenase-2: A Growing Class of Anti-Inflammatory Drugs Mol. Interv., April 1, 2001; 1(1): 30 - 38. [Abstract] [Full Text]
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D. Praticò, C. Tillmann, Z.-B. Zhang, H. Li, and G. A. FitzGerald Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice PNAS, March 1, 2001; (2001) 61607398. [Abstract] [Full Text]
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E. Fosslien Mitochondrial Medicine - Molecular Pathology of Defective Oxidative Phosphorylation Ann. Clin. Lab. Sci., January 1, 2001; 31(1): 25 - 67. [Abstract] [Full Text] [PDF]
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Q. Jiang, I. Elson-Schwab, C. Courtemanche, and B. N. Ames gamma -Tocopherol and its major metabolite, in contrast to alpha -tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells PNAS, September 22, 2000; (2000) 200357097. [Abstract] [Full Text]
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O. Belton, D. Byrne, D. Kearney, A. Leahy, and D. J. Fitzgerald Cyclooxygenase-1 and -2-Dependent Prostacyclin Formation in Patients With Atherosclerosis Circulation, August 22, 2000; 102(8): 840 - 845. [Abstract] [Full Text] [PDF]
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D. Pratico, Y. Cheng, and G. A. FitzGerald TP or Not TP: Primary Mediators in a Close Runoff? Arterioscler. Thromb. Vasc. Biol., July 1, 2000; 20(7): 1695 - 1698. [Full Text] [PDF]
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R. P. Phipps Atherosclerosis: The emerging role of inflammation and the CD40-CD40 ligand system PNAS, June 20, 2000; 97(13): 6930 - 6932. [Full Text] [PDF]
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E. M. Smyth, S. C. Austin, M. P. Reilly, and G. A. FitzGerald Internalization and Sequestration of the Human Prostacyclin Receptor J. Biol. Chem., October 6, 2000; 275(41): 32037 - 32045. [Abstract] [Full Text] [PDF]
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D. Pratico, C. Tillmann, Z.-B. Zhang, H. Li, and G. A. FitzGerald Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice PNAS, March 13, 2001; 98(6): 3358 - 3363. [Abstract] [Full Text] [PDF]
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