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From the Department of Medicine,*
Cardiovascular
Division, Brigham and Women’s Hospital, Harvard Medical School,
Boston, Massachusetts; the Department of Cardiovascular
Pathology,
Armed Forces Institute of
Pathology, Washington, District of Columbia; and the Department of
Medicine,
Washington University School of
Medicine, St. Louis, Missouri
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Macrophages play critical roles in atherogenesis1,17,18 and participate in the pathogenesis of the acute coronary syndromes.19-21 Their pro-inflammatory properties likely contribute to destabilization of atheroma by promoting extracellular matrix (ECM) degradation and hence superficial erosion or rupture of plaques, causes of episodic progression of atherosclerosis and, ultimately, of occlusive thrombus formation.21-23 During atherogenesis, circulating monocytes migrate into the arterial wall andmature into macrophages whose functional properties probably depend on the local microenvironment.17,18,20,24 Daugherty and colleagues2 found that macrophages in human atheroma contain MPO. However, traditional sources of MPO include blood neutrophils but not tissue macrophages,7,25 thus raising the possibility that lesional macrophages in human atheroma differ in this respect in vivo and that MPO-containing macrophages might play a special role in pathogenesis of atherosclerosis by producing the MPO-derived reactive oxygen species, HOCl.
We hypothesized that MPO-containing macrophages and HOCl derived from these cells might influence atherosclerotic plaque stability. To test this hypothesis, we investigated the expression of MPO in various stagesof human atherosclerosis and the factor(s) that mayregulate macrophage MPO expression in human atherosclerosis. Our results indicate that MPO-containing macrophages might contribute to atherogenesis and particularly the acute coronary syndromes by augmentingoxidative stress.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human Arterial Samples
Human nonatherosclerotic arteries and atherosclerotic arteries (coronary arteries, carotid arteries, and aortas) were obtained from patients who underwent transplantation and carotid endarterectomy or from autopsy. The arteries were immediately rinsed with phosphate-buffered saline (PBS), embedded in OCT compound, and stored at -80°C. Ruptured or eroded coronary arteries were obtained from sudden cardiac death patients and fixed in formaldehyde. We histologically classified these into nondiseased arteries (n = 7), diffuse intimal thickening (type I, n = 14), fatty streaks (type II, n = 14), atheromatous plaques (type Va, n = 25), fibromuscular plaques (type Vc, n = 17), eroded plaques (type VI, n = 7), and ruptured plaques (type VI, n = 8) by the American Heart Association histological criteria.
Immunohistochemistry
Frozen sections were cut in 6-µm-thick sections and fixed in 4% paraformaldehyde. Paraffin sections of ruptured or erosive plaques were cut in 6-µm-thick sections, dewaxed in xylene, and rehydrated in ethanol. The sections were incubated in 0.5% bovine serum albumin, 2.5% nonfat dried milk, 5% nonimmune serum/PBS for 30 minutes to block nonspecific binding of the primary antibody. Nonspecific avidin and biotin binding was diminished by AB-blocking reagent. Sections were incubated for 1 hour at room temperature with the primary antibodies and immunostaining was performed with an avidin-biotin-alkaline phosphatase system with fast red as a chromogen. In some experiments, we performed double immunostaining using pAb MPO as the first primary antibody and mAb CD68 or CD66b as the second primary antibody. At first, MPO immunoreactivity was detected by an avidin-biotin-alkaline phosphatase system (red), and then the sections were treated with AB-blocking reagent again and incubated with the second primary antibody at 4°C overnight. The next day, the second target immunoreactivity was detected by an avidin-biotin-glucose oxidase system (blue). (dilution of antibodies: 1:250 for MPO, CD68; 1:300 for GM-CSF; 1:100 for CD66b; 1:10 for HOP-1). Nuclei were counterstained with hematoxylin for single staining or with methyl green for double staining. By examining low-power fields (x100) in serial sections, MPO-positive cells were counted and GM-CSF-immunoreactive areas were selected and quantitated by computer-assisted image analysis (Image-Pro Plus, Media Cybernetics). Linear regression analysis was performed to examine the correlation between the number of MPO-positive cells (cells/low-power field) and GM-CSF-immunoreactive areas (mm2/low-power field).
Isolation of Human Monocytes
Human peripheral blood mononuclear cells were isolated from plateletpheresis residues of normal donors (provided by Dr. Steven Clinton at the Dana-Farber Cancer Institute) by Ficoll density gradient centrifugation (density = 1.077 g/ml, 400 x g for 45 minutes). The mid-layer cells were collected and suspended in Ca, Mg-free Hanks’ balanced salt solution. The mononuclear cells were again overlayered on separation media (density = 1.070 g/ml) and recentrifuged for 15 minutes at 400 x g to separate a lymphocyte-rich fraction and to limit neutrophil contamination in the monocyte-rich fraction. After centrifugation, the monocyte-rich fraction was collected from the mid-floating layer, and the cells were plated on 6-well plates (Falcon 3046, Falcon, Oxnard, CA) and incubated for 1 hour at 37°C to allow adhesion. Then, the preparation was washed three times with Hanks’ balanced salt solution and the remaining adherent cells were used as freshly isolated monocytes or cultured in Medium-199 containing penicillin/streptomycin with or without various factors for the days indicated. The monocyte content of this preparation is >92% as determined by flow cytometry using mAb CD68.
MPO Activity Assay
Monocytes and monocyte-derived macrophages were harvested with buffer A [(10 mmol/L phosphate buffer containing phenylmethylsulfonyl fluoride (1 mmol/L), leupeptin (100 µmol/L), pepstatin A (1 µmol/L), and cetyltrimethylammonium bromide (0.5%) pH = 7.0]. The samples were sonicated at 4°C. DNA content was measured in the total cell lysate.27 The cell lysate was centrifuged at 400 x g for 10 minutes and the supernatant was used for MPO activity assays and Western blotting. Peroxidase activity in the cell lysate was measured by the guaiacol peroxidation method2 and MPO activity was calculated from NaN3-inhibitable peroxidase activity using purified MPO as a standard. In situ endogenous peroxidase activity in atherosclerotic tissue was examined by diaminobenzidine or tetramethylbenzidine as the reducing substrate. Atheromatous carotid plaques and nondiseased aortas were homogenized in buffer A and centrifuged at 3000 x g for 10 minutes. In the supernatant, NaN3-inhibitable peroxidase activity was measured by tetramethylbenzidine peroxidation method and protein concentration was determined by bicinchoninic acid kit (Pierce, Rockford, IL).
Western Blotting
Human nondiseased aorta and atheromatous carotid arteries were homogenized in buffer A and centrifuged at 400 x g for 10 minutes. The supernatant was collected as the total arterial extract. MPO in the cell lysate, and the total arterial extract were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and blotted onto polyvinylidene difluoride membranes (Bio-Rad, Richmond, CA) with a semidry blotting apparatus. Nonspecific binding was reduced by blocking buffer (5% nonfat dry milk, 2% normal serum, 0.1% Tween20/PBS), and the primary (1:250 anti-MPO and 1:250 anti-GM-CSF) and peroxidase-conjugated secondary (1:4,000 anti-rabbit-IgG and 1:5,000 anti-mouse-IgG from Jackson ImmunoResearch, West Grove, PA) antibodies were diluted in the blocking buffer. Blots were incubated in chemiluminescence reagent (DuPont-New England Nuclear Life Science, Boston, MA) and visualized by exposure to X-ray film.
Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) Analysis of MPO and GM-CSF-mRNA Expression
Total RNA was extracted from HL-60 cells, arterial tissues, monocytes, and macrophages. Total RNA (5 µg) was used for cDNA synthesis, and the reverse transcriptase reaction mixture (2 µl) was used for PCR reaction with a DNA thermal cycler for 40 cycles (30 seconds at 92°C, 30 seconds at 56°C, and 2 minutes at 72°C). Identical reactions were also set up in the absence of reverse transcriptase for control experiments and these control reactions yielded the negative results, indicating no genomic contamination (data not shown). Primers: G3PDH sense 5'-ACCACAGTCCATGCCATCAC-3', antisense 5'-TCCACCACCCTGTTGCTGTA-3'; MPO sense 5'-GACACCTCGTTGGTGCTGAG-3', antisense 5'-TCGCAGTTGACGCCAGTGC-3'; GM-CSF sense 5'-CCTGAACCTGAGTAGAGACAC-3', antisense 5'-TCCCATTCTTCTGCCATGCCT-3'. The amplified PCR products (G3PDH, 452 bp; MPO, 674 bp; GM-CSF, 484 bp) were electrophoresed in 1.5% agarose gels and visualized by ethidium bromide staining.
Assay of HOCl Production and MPO Degranulation from Macrophages
HOCl production from macrophages was determined as reported
previously.28
GM-CSF-treated macrophages were stimulated
by various stimuli [phorbol myristate acetate (PMA), opsonized
zymosan, A23187, norepinephrine, interleukin-1ß (IL-1ß), tumor
necrosis factor-
, interferon-
, lysophosphatidylcholine (lysoPC),
CD40L, or cholesterol crystals] in Krebs-Henseleit buffer solution
(pH = 7.4) containing taurine (20 mmol/L) at 37°C for 2 hours.
The concentration of HOCl-mediated product, taurine chloramine, in the
incubation medium was determined by Ellman’s Reagent. MPO levels in
the culture medium were determined by MPO-specific enzyme-linked
immunosorbent assay (Calbiochem, La Jolla, CA). Cells were harvested by
PBS-ethylenediaminetetraacetic acid to measure DNA
content.27
Statistical Analysis
Data in figures represent the means ± SD of the indicated number of samples. The mean values for more than three groups were compared by analysis of variance. The difference between two mean values was analyzed with the unpaired Student’s t-test. A value of P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent studies have demonstrated the presence of enzymatically
active MPO in human atherosclerosis.2
Advanced
atheromatous plaques (type Va, n = 25) consistently
expressed abundant MPO immunoreactivity in intimal mononuclear cells
(Figure 1, A and B)
, and human
atherosclerotic lesions expressed MPO variably depending on the stage
of disease (Table 1
and Figure 1A
).
Advanced atheromatous lesions contained MPO-positive cells particularly
in the fibrous cap, near microvessels, and in the lipid core (Figure 1B)
. Arteries with diffuse intimal thickening (n
= 14), fatty streaks (n = 14), and fibromuscular
plaques (n = 17) generally exhibited little MPO
immunoreactivity, although some of these specimens did contain
MPO-containing cells (Table 1
and Figure 1A
). Advanced fibromuscular
plaques (type Vc) contained MPO-positive cells in the subendothelial
space and deep intimal region (Figure 1B)
. Most MPO-containing cells
were not lipid-laden foam cells, but some lipid-laden foam cells were
also MPO-positive. Arteries that showed no signs of disease
(n = 7) all lacked MPO immunoreactivity (data
not shown).
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To determine unambiguously which cells within human atheroma
express MPO, we performed double immunostaining using anti-MPO antibody
and cell-type specific antibodies (CD68 for macrophages and CD66b for
neutrophils). Intimal cells of human atherosclerotic arteries did not
express the neutrophil marker CD66b (data not shown). The MPO-positive
cells in atherosclerotic lesions were mononuclear cells and reacted
with CD68, identifying these cells as macrophages (Figure 2
, arrowheads). Fatty streaks contained
many CD68-positive intimal mononuclear cells but few MPO-containing
cells (Figure 2
, left). In contrast, many cells in advanced
atheromatous plaques were positive for both MPO and CD68, although some
CD68-positive macrophages lacked MPO (Figure 2
, right). Thus, human
atherosclerotic lesions contained two phenotypes of macrophages, one
MPO-positive and the other MPO-negative.
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Most myocardial infarctions are caused by thrombosis on the
substrate of a disrupted atherosclerotic plaque.22,23
Major mechanisms of plaque disruption include fracture of the fibrous
cap22
and superficial erosion of the endothelial cells
lining the artery wall.21
We therefore studied culprit
lesions of both types in coronary arteries from victims of sudden
cardiac death. Sites of plaque rupture in the fibrous caps
(n = 8) and superficial erosions
(n = 7) in coronary arteries from victims of
sudden cardiac death exhibited abundant MPO-containing mononuclear
cells (Figure 3
and Table 1
). We found
significantly increased numbers of MPO-positive macrophages at sites of
eroded or ruptured plaques (Table 1
, P < 0.01). In
eroded or ruptured plaques, few neutrophils (CD66b-positive cells)
localized at the sites of erosion or rupture, although the occlusive
thrombi do contain occasional neutrophils (data not shown).
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We used freshly isolated and cultured human monocytes to explore
mechanisms that might regulate MPO expression in macrophages. Culturing
adherent monocytes in medium supplemented with human serum (5%) caused
an initial rapid loss of both MPO activity and protein that was almost
complete by 3 days as reported previously.29
Similar
results were observed when serum concentrations varied from 5 to 20%
(data not shown). GM-CSF and, to a lesser extent, IL-3 preserved MPO
activity during the 7-day culture period, whereas M-CSF was inactive in
this regard (Figure 4A)
. Retention of MPO
activity depended on GM-CSF concentration (10 to 500 U/ml) (Figure 4B)
and the GM-CSF-treated macrophages (but not human serum-treated
macrophages or M-CSF-treated macrophages) contained MPO protein (Figure 4C)
. These results indicate that GM-CSF selectively regulates MPO
levels during differentiation of circulating monocytes into
macrophages. RT-PCR detected MPO mRNA in cultured HL-60 cells but not
in human atherosclerotic tissue, monocytes, or monocyte-derived
macrophages (data not shown).
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Advanced atheromatous plaques (type Va) consistently exhibited
considerable GM-CSF immunoreactivity in the intima
(n = 15) (Figure 5A)
. The advanced carotid artery
atheroma, but not nondiseased aorta, expressed GM-CSF protein and
GM-CSF mRNA (Figure 5, B and C)
. MPO-positive macrophages localized in
the GM-CSF-expressing atherosclerotic intima (Figure 5D)
. Depending on
the stage of disease, human atherosclerotic lesions also variably
expressed GM-CSF in the intima; arteries with fatty streaks
(n = 8), and fibromuscular plaques
(n = 12) varied but generally exhibited little
immunoreactive GM-CSF (data not shown). We furthermore found that the
areas of immunoreactive GM-CSF and the number of MPO-positive
macrophages correlated significantly in human atherosclerotic lesions
(R2
= 0.84, P
< 0.001 by linear regression analysis) (Figure 5E)
.
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In advanced atheromatous plaques, MPO immunoreactivity and
endogenous peroxidase activity co-localized intracellularly in the
intima and extracellularly in the lipid core (Figure 6A
, n = 12). Extracts of
human advanced atheroma (n = 5), but not of
nondiseased aortae (n = 4), contain MPO activity
(277 ± 143 mU/mg protein; range, 77 to 
825; n
= 5). Advanced human atheromatous plaques typically have a large
central hypocellular lipid-rich region.30,31
This lipid
core probably plays a key role in the biomechanical destabilization of
plaques and in thrombogenesis.17,22,23,32
Lipid cores of
advanced atherosclerotic lesions, especially lipid cores with gruel,
contained both MPO immunoreactivity and endogenous peroxidase activity
(Figure 6A)
. The in situ endogenous peroxidase activity was
inhibited by the heme poison NaN3 and by a
polyclonal antibody to MPO (data not shown). We also found that the
endogenous peroxidase activity and immunoreactive HOCl-modified
proteins co-localized in the intima of advanced atheroma (Figure 6B)
.
Specifically, thin fibrous caps, zones surrounding the necrotic lipid
core, and fragmented ECM in atheroma contain HOCl-modified protein
epitopes (Figure 6B)
. The MPO-poor fibromuscular plaques examined
(n = 17) contained few HOCl-modified proteins
(data not shown). HOCl-modified protein immunoreactivity was prominent
at the sites of ruptured fibrous caps (n = 8) or
eroded plaques (n = 7) of acute coronary
syndromes (Figure 6C)
.
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To investigate the possibility that MPO-containing macrophages may
mediate oxidative stress and trigger inflammatory events in
atherosclerotic lesions, we examined the behavior of macrophages
treated with GM-CSF in vitro. The cells chlorinated
extracellular taurine in response to PMA and to opsonized zymosan
(Figure 7)
and PMA provoked MPO release
from macrophages, presumably by degranulation (medium MPO levels:
vehicle, 1.0 ± 0.2; PMA, 21.2 ± 3.1 ng/ml;
n = 3; P < 0.01). Pathophysiological
stimuli known to be present in human atherosclerotic plaques,
CD40L,33
lysoPC,34
or cholesterol
crystals,30
induced HOCl-release from GM-CSF-treated
macrophages (Figure 7)
and MPO release from macrophages in
vitro (medium MPO levels: vehicle, 1.0 ± 0.2; CD40L,
17.5 ± 2.6; cholesterol crystals, 12.1 ± 1.8; lysoPC,
14.8 ± 2.2 ng/ml; n = 3; P <
0.01).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Acute coronary syndromes involve the remodeling of arterial ECM and the erosion of plaques or rupture of the fibrous cap.19-23 Recently, several studies have implicated lesional macrophages in ECM degradation because of production of matrix metalloproteinases (MMPs),35,36 inhibitors of metalloproteinases (the TIMPs), and because the MMP pro-enzymes require extracellular activation.37 Therefore, increased MMP synthesis alone may not suffice for tissue destruction; activation of pro-MMPs and a shift in the MMP-TIMP balance would need to prevail at sites of pathological ECM degradation. The present study demonstrates that MPO-positive macrophages generate HOCl and that the fragmented ECM in atheroma contains HOCl-modified protein. HOCl can inactivate TIMP-138 and HOCl can activate pro-MMPs,39,40 that are expressed in human atheroma.35,36 Thus, the MPO-containing macrophages could play a special role in ECM degradation by acceleration of proteinase cascade through oxidative stress. Our observation that MPO-containing macrophages and HOCl-modified proteins localize in the fibrous cap and HOCl itself can solubilize collagen41,42 also suggest that these macrophages may contribute to structural weakening of the fibrous cap and plaque rupture independent of proteolysis. MPO-positive macrophages localized in subendothelial space in some advanced fibromuscular plaques and HOCl itself can degrade proteoglycan,43 decrease adhesiveness of subendothelial ECM to endothelial cells,44 and cause endothelial cell retraction and death.45 Each of these functions may promote local endothelial desquamation that produces superficial erosion of the intima, an important cause of coronary thrombosis in fibromuscular plaques. We also found significantly increased numbers of these MPO-positive macrophages and presence of HOCl-modified proteins in the culprit lesions of acute coronary syndromes. Taken together, these observations indicate that the lesional MPO-containing macrophages may participate in the development of acute coronary syndromes.
Morphologically, so-called "vulnerable" or unstable plaques have a thin fibrous cap and a large lipid core (atheromatous plaque, type Va), and so-called "stable" plaques have a thick fibrous cap, abundant ECM, and smooth muscle cells with low lipid content (fibromuscular plaque, type Vc).19,32,46 We found many MPO-containing macrophages in the advanced atheromatous plaques ("unstable plaques") and observed that macrophages of this phenotype accumulated locally at sites of rupture in coronary plaques. Some fibromuscular plaques with morphological features of stability also locally contained numerous MPO-containing macrophages in the subendothelial space. Eroded coronary fibromuscular plaques have similar levels of MPO-containing macrophages, as do atheromatous plaques, suggesting that accumulated MPO-containing macrophages locally destabilized the fibromuscular plaques. Thus, the present observations support a novel concept that local accumulation of MPO-containing macrophages in plaques could influence atheroma stability irrespective of the dominant plaque morphology, and in that manner govern a plaque’s propensity to provoke thrombosis.
Although most atheroma exhibit features of chronic inflammation,47 the actual triggers of the acute local inflammation that leads to clinical symptoms remain unclear. For MPO-positive macrophages to realize their pro-inflammatory capacity in the arterial wall, they must release MPO into the extracellular space. The stimuli for and mechanisms of this degranulation remain unknown. We demonstrate here that CD40L, lysoPC, or cholesterol crystals, stimuli found in human atheroma,30,33,34 can trigger the release of MPO and HOCl production from MPO-positive macrophages in vitro. Thus, the activation of MPO-containing macrophages and subsequent degranulation might contribute to the transition to acute complications of atheroma. The present findings that PMA (a potent PKC activator) induced the HOCl production from MPO-positive macrophages in vitro suggest possible signaling pathways.
Our data underscore macrophage heterogeneity.17,18,20,24 We identified two phenotypes of macrophages in human atherosclerotic lesions, one MPO-positive and the other MPO-negative. Previously, Owen and colleagues48 and Akiyama and colleagues49 reported the existence of two distinct monocyte populations, high MPO and low MPO monocytes, in circulating human blood. The present observations demonstrate a similar dichotomy of macrophage phenotype in human atherosclerosis in vivo. MPO-containing macrophages in plaques might arise from the high MPO monocytes in circulating blood through selective survival and differentiation if local environmental factors maintained their phenotype. We demonstrate here that GM-CSF, but not M-CSF, preserves MPO activity in human monocyte-derived macrophages in vitro. We also show that MPO-positive macrophages localize in the GM-CSF-expressing atherosclerotic intima and localize abundant GM-CSF within the atheroma. These observations suggest a specific role of GM-CSF in the regulation of macrophage phenotype in human atherosclerosis. Alternatively, the MPO-positive macrophages might arise from preferential recruitment into atheroma. Human atheromata contain several chemokines, including monocyte chemoattractant protein-1, IP-10, Mig, SDF, I-TAC, or IL-8.50-52 Circulating mononuclear cells have heterogeneous chemokine receptor expression.53 The notion that this heterogeneity might selectively recruit high MPO monocytes into atherosclerotic arteries requires further investigation.
We demonstrated that advanced human atheromatous plaques expressed GM-CSF-protein and mRNA in the present study. We have not yet formally identified the cell types that express GM-CSF in the arterial wall. However, all types of atheroma-associated cells, endothelial cells, macrophages, smooth muscle cells, and T-lymphocytes can produce GM-CSF.54,55 Moreover, bioactive GM-CSF can bind to extracellular proteoglycans and retain biological activity.56 Thus, GM-CSF is synthesized locally in the artery wall and stored extracellularly in proteoglycan-rich plaques. Elucidation of the mechanisms that regulate GM-CSF expression in atherosclerosis will require further study.
The underlying mechanisms of MPO expression in human atherosclerosis remain uncertain. However, the absence of detectable MPO mRNA in atheroma suggests that transcription of MPO gene and de novo synthesis of MPO protein in the arterial wall contribute little to MPO expression in atherosclerosis. MPO is a stable and highly cationic protein that binds readily to negatively charged ECM components such as glysaminoglycans and proteoglycans. This property may permit accumulation and persistence of biologically active MPO protein in the atherosclerotic plaques.
Many lines of evidence indicate production of HOCl by MPO in human
atherosclerosis.3-6
We show here the presence of
HOCl-modified proteins within advanced atheroma and particularly in
culprit lesions of acute coronary syndromes. These findings support the
pathological significance of HOCl production in atherogenesis. We
cannot ascertain the actual local in vivo concentrations of
hypochlorous anion produced in atherosclerotic lesions. The present
study showed that cultured MPO-positive macrophages produce 7.5 pmol
HOCl/103
cells/hour, and the ruptured plaques
contain 118 ± 25 MPO-positive macrophages/low-power field. HOCl
can rapidly react with next target molecules at the site of its
generation. Hypochlorous anion within the extracellular space may reach
approximately millimolar concentrations during moderate
inflammation.8
In conclusion, we provide evidence that a distinct phenotype of macrophages that expresses MPO localized in human atherosclerosis and the culprit lesions of acute coronary syndromes. We identify GM-CSF as an endogenous mediator that may favor accumulation of macrophages of this phenotype in atheroma. Such pro-inflammatory macrophages could play a particular role in the pathogenesis of human atherosclerosis and acute coronary syndromes by contributing to oxidative stress.
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Acknowledgements |
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Footnotes |
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Supported by grants from National Heart, Lung, and Blood Institute (HL34636 to P. L. and AG12293 and AG15013 to J. W. H.).
Portions of this work were presented in preliminary form at the Annual Scientific Session of the American Heart Association in 1997 (Circulation 1997;96: I-417) and 1998 (Circulation 1998;98: I-315).
S. S. is the recipient of Banyu Fellowship Awards in Lipid Metabolism and Atherosclerosis from Banyu Pharmaceutical Co., Ltd. and the Merck Company Foundation. J. W. H. is an Established Investigator of the American Heart Association.
Accepted for publication November 21, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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J. Shih, S. A. Datwyler, S. C. Hsu, M. S. Matias, D. P. Pacenti, C. Lueders, C. Mueller, O. Danne, and M. Mockel Effect of Collection Tube Type and Preanalytical Handling on Myeloperoxidase Concentrations Clin. Chem., June 1, 2008; 54(6): 1076 - 1079. [Abstract] [Full Text] [PDF]
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 R Tsuru, H Kondo, Y Hojo, M Gama, O Mizuno, T Katsuki, K Shimada, M Kikuchi, and T Yashiro Increased granzyme B production from peripheral blood mononuclear cells in patients with acute coronary syndrome Heart, March 1, 2008; 94(3): 305 - 310. [Abstract] [Full Text] [PDF]
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 G. Brevetti, V. Schiano, E. Laurenzano, G. Giugliano, M. Petretta, F. Scopacasa, and M. Chiariello Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease Eur. Heart J., January 2, 2008; 29(2): 224 - 230. [Abstract] [Full Text] [PDF]
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 L. G. Spagnoli, E. Bonanno, G. Sangiorgi, and A. Mauriello Role of Inflammation in Atherosclerosis J. Nucl. Med., November 1, 2007; 48(11): 1800 - 1815. [Abstract] [Full Text] [PDF]
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 J. Ohayon, O. Dubreuil, P. Tracqui, S. Le Floc'h, G. Rioufol, L. Chalabreysse, F. Thivolet, R. I. Pettigrew, and G. Finet Influence of residual stress/strain on the biomechanical stability of vulnerable coronary plaques: potential impact for evaluating the risk of plaque rupture Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1987 - H1996. [Abstract] [Full Text] [PDF]
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 A. N. MacRitchie, A. A. Gardner, S. M. Prescott, and D. M. Stafforini Molecular basis for susceptibility of plasma platelet-activating factor acetylhydrolase to oxidative inactivation FASEB J, April 1, 2007; 21(4): 1164 - 1176. [Abstract] [Full Text] [PDF]
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A. Zirlik, C. Maier, N. Gerdes, L. MacFarlane, J. Soosairajah, U. Bavendiek, I. Ahrens, S. Ernst, N. Bassler, A. Missiou, et al. CD40 Ligand Mediates Inflammation Independently of CD40 by Interaction With Mac-1 Circulation, March 27, 2007; 115(12): 1571 - 1580. [Abstract] [Full Text] [PDF]
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Z. Shaposhnik, X. Wang, M. Weinstein, B. J. Bennett, and A. J. Lusis Granulocyte Macrophage Colony-Stimulating Factor Regulates Dendritic Cell Content of Atherosclerotic Lesions Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 621 - 627. [Abstract] [Full Text] [PDF]
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J. Xu, Z. Xie, R. Reece, D. Pimental, and M.-H. Zou Uncoupling of Endothelial Nitric Oxidase Synthase by Hypochlorous Acid: Role of NAD(P)H Oxidase-Derived Superoxide and Peroxynitrite Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2688 - 2695. [Abstract] [Full Text] [PDF]
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F. D. Kolodgie, A. P. Burke, K. S. Skorija, E. Ladich, R. Kutys, A. T. Makuria, and R. Virmani Lipoprotein-Associated Phospholipase A2 Protein Expression in the Natural Progression of Human Coronary Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2523 - 2529. [Abstract] [Full Text] [PDF]
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M. Ditiatkovski, B.-H. Toh, and A. Bobik GM-CSF Deficiency Reduces Macrophage PPAR-{gamma} Expression and Aggravates Atherosclerosis in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2337 - 2344. [Abstract] [Full Text] [PDF]
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L. W. Castellani, J. J. Chang, X. Wang, A. J. Lusis, and W. F. Reynolds Transgenic mice express human MPO -463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in -463G males J. Lipid Res., July 1, 2006; 47(7): 1366 - 1377. [Abstract] [Full Text] [PDF]
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 K. R. Wildsmith, C. J. Albert, D. S. Anbukumar, and D. A. Ford Metabolism of Myeloperoxidase-derived 2-Chlorohexadecanal J. Biol. Chem., June 23, 2006; 281(25): 16849 - 16860. [Abstract] [Full Text] [PDF]
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V. A. Cameron, T. J. Mocatta, A. P. Pilbrow, C. M. Frampton, R. W. Troughton, A. M. Richards, and C. C. Winterbourn Angiotensin Type-1 Receptor A1166C Gene Polymorphism Correlates With Oxidative Stress Levels in Human Heart Failure Hypertension, June 1, 2006; 47(6): 1155 - 1161. [Abstract] [Full Text] [PDF]
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 R. Virmani, A. P. Burke, A. Farb, and F. D. Kolodgie Pathology of the vulnerable plaque. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C13 - C18. [Abstract] [Full Text] [PDF]
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S. Tsimikas, J. T. Willerson, and P. M. Ridker C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C19 - C31. [Abstract] [Full Text] [PDF]
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S. Baldus, V. Rudolph, M. Roiss, W. D. Ito, T. K. Rudolph, J. P. Eiserich, K. Sydow, D. Lau, K. Szocs, A. Klinke, et al. Heparins Increase Endothelial Nitric Oxide Bioavailability by Liberating Vessel-Immobilized Myeloperoxidase Circulation, April 18, 2006; 113(15): 1871 - 1878. [Abstract] [Full Text] [PDF]
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F. A. Jaffer, P. Libby, and R. Weissleder Molecular and Cellular Imaging of Atherosclerosis: Emerging Applications J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1328 - 1338. [Abstract] [Full Text] [PDF]
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J. Takeshita, J. Byun, T. Q. Nhan, D. K. Pritchard, S. Pennathur, S. M. Schwartz, A. Chait, and J. W. Heinecke Myeloperoxidase Generates 5-Chlorouracil in Human Atherosclerotic Tissue: A POTENTIAL PATHWAY FOR SOMATIC MUTAGENESIS BY MACROPHAGES J. Biol. Chem., February 10, 2006; 281(6): 3096 - 3104. [Abstract] [Full Text] [PDF]
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R. De Palma, F. Del Galdo, G. Abbate, M. Chiariello, R. Calabro, L. Forte, G. Cimmino, M. F. Papa, M. G. Russo, G. Ambrosio, et al. Patients With Acute Coronary Syndrome Show Oligoclonal T-Cell Recruitment Within Unstable Plaque: Evidence for a Local, Intracoronary Immunologic Mechanism Circulation, February 7, 2006; 113(5): 640 - 646. [Abstract] [Full Text] [PDF]
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M. M. McCormick, F. Rahimi, Y. V. Bobryshev, K. Gaus, H. Zreiqat, H. Cai, R. S. A. Lord, and C. L. Geczy S100A8 and S100A9 in Human Arterial Wall: IMPLICATIONS FOR ATHEROGENESIS J. Biol. Chem., December 16, 2005; 280(50): 41521 - 41529. [Abstract] [Full Text] [PDF]
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A. Daugherty, N. R. Webb, D. L. Rateri, and V. L. King Thematic review series: The Immune System and Atherogenesis. Cytokine regulation of macrophage functions in atherogenesis J. Lipid Res., September 1, 2005; 46(9): 1812 - 1822. [Abstract] [Full Text] [PDF]
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 J. Garcia de Tena, I. Kriszbacher, M. Koppan, J. Bodis, and G. K. Hansson Inflammation, Atherosclerosis, and Coronary Artery Disease N. Engl. J. Med., July 28, 2005; 353(4): 429 - 430. [Full Text] [PDF]
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S. J. Nicholls and S. L. Hazen Myeloperoxidase and Cardiovascular Disease Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1102 - 1111. [Abstract] [Full Text] [PDF]
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T. S. McMillen, J. W. Heinecke, and R. C. LeBoeuf Expression of Human Myeloperoxidase by Macrophages Promotes Atherosclerosis in Mice Circulation, May 31, 2005; 111(21): 2798 - 2804. [Abstract] [Full Text] [PDF]
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 H. Hakonarson, S. Thorvaldsson, A. Helgadottir, D. Gudbjartsson, F. Zink, M. Andresdottir, A. Manolescu, D. O. Arnar, K. Andersen, A. Sigurdsson, et al. Effects of a 5-Lipoxygenase-Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction: A Randomized Trial JAMA, May 11, 2005; 293(18): 2245 - 2256. [Abstract] [Full Text] [PDF]
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F. S. Apple, A. H.B. Wu, J. Mair, J. Ravkilde, M. Panteghini, J. Tate, F. Pagani, R. H. Christenson, M. Mockel, O. Danne, et al. Future Biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome Clin. Chem., May 1, 2005; 51(5): 810 - 824. [Abstract] [Full Text] [PDF]
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P. K. Witting, B. J. Wu, M. Raftery, P. Southwell-Keely, and R. Stocker Probucol Protects against Hypochlorite-induced Endothelial Dysfunction: IDENTIFICATION OF A NOVEL PATHWAY OF PROBUCOL OXIDATION TO A BIOLOGICALLY ACTIVE INTERMEDIATE J. Biol. Chem., April 22, 2005; 280(16): 15612 - 15618. [Abstract] [Full Text] [PDF]
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B. Shao, C. Bergt, X. Fu, P. Green, J. C. Voss, M. N. Oda, J. F. Oram, and J. W. Heinecke Tyrosine 192 in Apolipoprotein A-I Is the Major Site of Nitration and Chlorination by Myeloperoxidase, but Only Chlorination Markedly Impairs ABCA1-dependent Cholesterol Transport J. Biol. Chem., February 18, 2005; 280(7): 5983 - 5993. [Abstract] [Full Text] [PDF]
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R. Stocker, A. Huang, E. Jeranian, J. Y. Hou, T. T. Wu, S. R. Thomas, and J. F. Keaney Jr Hypochlorous Acid Impairs Endothelium-Derived Nitric Oxide Bioactivity Through a Superoxide-Dependent Mechanism Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 2028 - 2033. [Abstract] [Full Text] [PDF]
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S. Pennathur, C. Bergt, B. Shao, J. Byun, S. Y. Kassim, P. Singh, P. S. Green, T. O. McDonald, J. Brunzell, A. Chait, et al. Human Atherosclerotic Intima and Blood of Patients with Established Coronary Artery Disease Contain High Density Lipoprotein Damaged by Reactive Nitrogen Species J. Biol. Chem., October 8, 2004; 279(41): 42977 - 42983. [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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J. A. Vita, M.-L. Brennan, N. Gokce, S. A. Mann, M. Goormastic, M. H. Shishehbor, M. S. Penn, J. F. Keaney Jr, and S. L. Hazen Serum Myeloperoxidase Levels Independently Predict Endothelial Dysfunction in Humans Circulation, August 31, 2004; 110(9): 1134 - 1139. [Abstract] [Full Text] [PDF]
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S. L. Hazen Myeloperoxidase and Plaque Vulnerability Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1143 - 1146. [Full Text] [PDF]
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S. Sugiyama, K. Kugiyama, M. Aikawa, S. Nakamura, H. Ogawa, and P. Libby Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression: Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1309 - 1314. [Abstract] [Full Text] [PDF]
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C. Bergt, X. Fu, N. P. Huq, J. Kao, and J. W. Heinecke Lysine Residues Direct the Chlorination of Tyrosines in YXXK Motifs of Apolipoprotein A-I When Hypochlorous Acid Oxidizes High Density Lipoprotein J. Biol. Chem., February 27, 2004; 279(9): 7856 - 7866. [Abstract] [Full Text] [PDF]
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A. P. Kumar, F. J. Piedrafita, and W. F. Reynolds Peroxisome Proliferator-activated Receptor {gamma} Ligands Regulate Myeloperoxidase Expression in Macrophages by an Estrogen-dependent Mechanism Involving the -463GA Promoter Polymorphism J. Biol. Chem., February 27, 2004; 279(9): 8300 - 8315. [Abstract] [Full Text] [PDF]
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M.-L. Brennan, M. S. Penn, F. Van Lente, V. Nambi, M. H. Shishehbor, R. J. Aviles, M. Goormastic, M. L. Pepoy, E. S. McErlean, E. J. Topol, et al. Prognostic Value of Myeloperoxidase in Patients with Chest Pain N. Engl. J. Med., October 23, 2003; 349(17): 1595 - 1604. [Abstract] [Full Text] [PDF]
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A. K. Thukkani, C. J. Albert, K. R. Wildsmith, M. C. Messner, B. D. Martinson, F.-F. Hsu, and D. A. Ford Myeloperoxidase-derived Reactive Chlorinating Species from Human Monocytes Target Plasmalogens in Low Density Lipoprotein J. Biol. Chem., September 19, 2003; 278(38): 36365 - 36372. [Abstract] [Full Text] [PDF]
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 W. Palinski United They Go: Conjunct Regulation of Aortic Antioxidant Enzymes During Atherogenesis Circ. Res., August 8, 2003; 93(3): 183 - 185. [Full Text] [PDF]
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X. Fu, S. Y. Kassim, W. C. Parks, and J. W. Heinecke Hypochlorous Acid Generated by Myeloperoxidase Modifies Adjacent Tryptophan and Glycine Residues in the Catalytic Domain of Matrix Metalloproteinase-7 (Matrilysin): AN OXIDATIVE MECHANISM FOR RESTRAINING PROTEOLYTIC ACTIVITY DURING INFLAMMATION J. Biol. Chem., August 1, 2003; 278(31): 28403 - 28409. [Abstract] [Full Text] [PDF]
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M. H. Shishehbor, M.-L. Brennan, R. J. Aviles, X. Fu, M. S. Penn, D. L. Sprecher, and S. L. Hazen Statins Promote Potent Systemic Antioxidant Effects Through Specific Inflammatory Pathways Circulation, July 29, 2003; 108(4): 426 - 431. [Abstract] [Full Text] [PDF]
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J. P. Henderson, J. Byun, J. Takeshita, and J. W. Heinecke Phagocytes Produce 5-Chlorouracil and 5-Bromouracil, Two Mutagenic Products of Myeloperoxidase, in Human Inflammatory Tissue J. Biol. Chem., June 20, 2003; 278(26): 23522 - 23528. [Abstract] [Full Text] [PDF]
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C. M. Dollery, C. A. Owen, G. K. Sukhova, A. Krettek, S. D. Shapiro, and P. Libby Neutrophil Elastase in Human Atherosclerotic Plaques: Production by Macrophages Circulation, June 10, 2003; 107(22): 2829 - 2836. [Abstract] [Full Text] [PDF]
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A. P. Burke, R. Virmani, Z. Galis, C. C. Haudenschild, and J. E. Muller Task force #2--what is the pathologic basis for new atherosclerosis imaging techniques? J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1874 - 1886. [Full Text] [PDF]
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M. H. Shishehbor, R. J. Aviles, M.-L. Brennan, X. Fu, M. Goormastic, G. L. Pearce, N. Gokce, J. F. Keaney Jr, M. S. Penn, D. L. Sprecher, et al. Association of Nitrotyrosine Levels With Cardiovascular Disease and Modulation by Statin Therapy JAMA, April 2, 2003; 289(13): 1675 - 1680. [Abstract] [Full Text] [PDF]
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T. Naruko, M. Ueda, K. Haze, A. C. van der Wal, C. M. van der Loos, A. Itoh, R. Komatsu, Y. Ikura, M. Ogami, Y. Shimada, et al. Neutrophil Infiltration of Culprit Lesions in Acute Coronary Syndromes Circulation, December 3, 2002; 106(23): 2894 - 2900. [Abstract] [Full Text] [PDF]
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B. J. Van Lenten, A. C. Wagner, G.M. Anantharamaiah, D. W. Garber, M. C. Fishbein, L. Adhikary, D. P. Nayak, S. Hama, M. Navab, and A. M. Fogelman Influenza Infection Promotes Macrophage Traffic Into Arteries of Mice That Is Prevented by D-4F, an Apolipoprotein A-I Mimetic Peptide Circulation, August 27, 2002; 106(9): 1127 - 1132. [Abstract] [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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 M Carlson, Y Raab, L Seveus, S Xu, R Hallgren, and P Venge Human neutrophil lipocalin is a unique marker of neutrophil inflammation in ulcerative colitis and proctitis Gut, April 1, 2002; 50(4): 501 - 506. [Abstract] [Full Text] [PDF]
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P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF]
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A. Shihabi, W.-G. Li, F. J. Miller Jr., and N. L. Weintraub Antioxidant therapy for atherosclerotic vascular disease: the promise and the pitfalls Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H797 - H802. [Full Text] [PDF]
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J. M. Upston, X. Niu, A. J. Brown, R. Mashima, H. Wang, R. Senthilmohan, A. J. Kettle, R. T. Dean, and R. Stocker Disease Stage-Dependent Accumulation of Lipid and Protein Oxidation Products in Human Atherosclerosis Am. J. Pathol., February 1, 2002; 160(2): 701 - 710. [Abstract] [Full Text] [PDF]
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M. O. Pentikainen, K. Oorni, and P. T. Kovanen Myeloperoxidase and Hypochlorite, but Not Copper Ions, Oxidize Heparin-Bound LDL Particles and Release Them From Heparin Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1902 - 1908. [Abstract] [Full Text] [PDF]
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K. E. Brown, E. M. Brunt, and J. W. Heinecke Immunohistochemical Detection of Myeloperoxidase and Its Oxidation Products in Kupffer Cells of Human Liver Am. J. Pathol., December 1, 2001; 159(6): 2081 - 2088. [Abstract] [Full Text] [PDF]
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R. Zhang, M.-L. Brennan, X. Fu, R. J. Aviles, G. L. Pearce, M. S. Penn, E. J. Topol, D. L. Sprecher, and S. L. Hazen Association Between Myeloperoxidase Levels and Risk of Coronary Artery Disease JAMA, November 7, 2001; 286(17): 2136 - 2142. [Abstract] [Full Text] [PDF]
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S. PFEIFFER, A. LASS, K. SCHMIDT, and B. MAYER Protein tyrosine nitration in mouse peritoneal macrophages activated in vitro and in vivo: evidence against an essential role of peroxynitrite FASEB J, November 1, 2001; 15(13): 2355 - 2364. [Abstract] [Full Text] [PDF]
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M. P. Herman, G. K. Sukhova, P. Libby, N. Gerdes, N. Tang, D. B. Horton, M. Kilbride, R. E. Breitbart, M. Chun, and U. Schonbeck Expression of Neutrophil Collagenase (Matrix Metalloproteinase-8) in Human Atheroma: A Novel Collagenolytic Pathway Suggested by Transcriptional Profiling Circulation, October 16, 2001; 104(16): 1899 - 1904. [Abstract] [Full Text] [PDF]
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A. MERTENS and P. HOLVOET Oxidized LDL and HDL: antagonists in atherothrombosis FASEB J, October 1, 2001; 15(12): 2073 - 2084. [Abstract] [Full Text] [PDF]
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E. Hurt-Camejo, G. Camejo, H. Peilot, K. Oorni, and P. Kovanen Phospholipase A2 in Vascular Disease Circ. Res., August 17, 2001; 89(4): 298 - 304. [Abstract] [Full Text] [PDF]
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S. Pfeiffer, A. Lass, K. Schmidt, and B. Mayer Protein Tyrosine Nitration in Cytokine-activated Murine Macrophages. INVOLVEMENT OF A PEROXIDASE/NITRITE PATHWAY RATHER THAN PEROXYNITRITE J. Biol. Chem., August 31, 2001; 276(36): 34051 - 34058. [Abstract] [Full Text] [PDF]
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X. Fu, S. Y. Kassim, W. C. Parks, and J. W. Heinecke Hypochlorous Acid Oxygenates the Cysteine Switch Domain of Pro-matrilysin (MMP-7). A MECHANISM FOR MATRIX METALLOPROTEINASE ACTIVATION AND ATHEROSCLEROTIC PLAQUE RUPTURE BY MYELOPEROXIDASE J. Biol. Chem., October 26, 2001; 276(44): 41279 - 41287. [Abstract] [Full Text] [PDF]
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