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From the Department of Psychiatry, Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The principal source of CRP and complement components has always been assumed to be liver. Up-regulation of CRP after tissue injuries such as acute myocardial infarcts14-17 has been attributed to induction of CRP in hepatocytes by inflammatory cytokines such as interleukin (IL)-6.18 CRP and the complement proteins are, however, ancient host-defense proteins whose phylogenetic origins can be traced back at least as far as the horseshoe crab.19,20 Therefore it would be anticipated that many tissues of the body would preserve their ability to generate these proteins as part of their innate immune defenses. Several types of cells have now been shown to produce complement proteins. We have recently shown that, in addition to complement proteins, the pentraxins CRP and amyloid P are generated in brain by neurons.21 The mRNAs for the pentraxins21 and the complement proteins22 are sharply up-regulated in the Alzheimer’s disease brain. In this article we show that arterial tissue itself produces CRP as well as complement proteins and that both the mRNAs and proteins are substantially up-regulated in atherosclerotic plaques. By in situ hybridization and immunohistochemistry, we show that the major producers are both smooth muscle-like cells in the swollen intima and macrophages. CRP is the most significantly up-regulated of all of these components, supporting the concept that CRP may be an endogenous activator of complement in atheromatous tissue.13
We also demonstrate the up-regulation in atherosclerotic plaques of two markers of tissue macrophages: the complement receptor CD11b and the MHC class II glycoprotein HLA-DR. These correlate with the infiltration of macrophages into the atheromata. Taken together, these data imply that a self-sustaining, localized inflammatory process is a major feature of atherosclerosis. They suggest that early anti-inflammatory therapy may be appropriate to arrest progression of the disease.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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lists the age, sex, postmortem delay,
cause of death, and tissues sampled for each of the cases. Tissue was
obtained from the pathology service of the University of British
Columbia Hospital under conditions approved by the University Human
Ethics Committee.
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500 mg
of each tissue sample, aliquots were subjected to single-strand cDNA
synthesis. To establish reliable parameters for determining comparative
mRNA levels using the RT-PCR technique, the method of Nakayama and
colleagues25
was followed. Graded amounts of cDNA, and
varying cycles of amplification, were used to determine for each cDNA
the range in which the logarithm of reaction product intensity was
linear to the amplification cycle number. All amplification experiments
were run in parallel with the cDNA of the housekeeping gene
cyclophilin. Cyclophilin was chosen as the internal standard because of
the consistency of its level from tissue to tissue and its postmortem
stability. A linear relationship was found between the logarithm of PCR
product intensity and cycle number for cyclophilin between 20 and 29
cycles, for CRP between 29 and 35 cycles, for all complement components
between 25 and 37 cycles, and for CD11b and HLA-DR between 29 and 35
cycles. The anticipated plateaus were reached beyond these cycle
numbers. In each case, cDNA was added in a range corresponding to 0.01
to 2 µg of total RNA. The product intensity was found to be
proportional to the amount of cDNA added. In all experiments, the
presence of possible contaminants was checked by control reactions in
which amplification was performed up to 35 cycles on samples in which
either reverse transcriptase or template cDNA was omitted from the
RT-PCR reaction mixture. No PCR product was obtained under these
conditions. After completion of preliminary experiments, standard
conditions were followed in which cDNA (1 µl) corresponding to 0.1
µg total RNA was added, and the cyclophilin product amplified for 27
cycles, the complement components and CRP for 35 cycles, and both CD11b
and HLA-DR for 30 cycles. Each PCR reaction product was electrophoresed
through a 6% polyacrylamide gel, the product visualized by incubation
with ethidium bromide, and the intensity of the bands imaged using a
GDS 7600 image analyzer (Ultra Violet Products, Uplands, CA). The
relative intensities of the bands were expressed as optical density
units.
The primers for complement proteins and cyclophilin were those
previously described.22,24
Table 2
lists the primers for CRP, CD11b, and
HLA-DR, the GenBank accession numbers, the product length, the
restriction enzyme used for digestion analysis, and the digestion
fragments obtained.
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Membranes were blocked in 5% skim milk for 2 hours. The immunoblots were then treated for 2 hours at room temperature with a primary antibody, followed by treatment for 1 hour with an appropriate secondary antibody labeled with horseradish peroxidase. Immunoreactivity was visualized by incubation with Supersignal CL-HRP chemiluminescent substrate (Pierce Chemical Co., Rockford, IL). The antibodies used for detection of the complement proteins were as previously described.22 Sheep anti-CRP (1:1,000 dilution) was obtained from Wako, mouse anti-HLA-DR1: 100 from DAKO (Carpinteria, CA), and mouse anti-CD11b (1:100) from Serotec (Raleigh, NC).
C4 and CRP cRNA probes were prepared starting with the RT-PCR products. The 256-bp C4 cDNA fragment was subcloned into the pGEM-T Easy plasmid vector (Promega, Madison, WI). The product was linearized with SpeI and NcoI (NEB) to produce sense and antisense DNA templates, respectively. The C4 cRNA probes were synthesized at 37°C for 3 hours in a mixture composed of 1 µg of linearized template DNA; 2 µl of ATP, CTP, GTP, and digoxigenin (DIG)-labeled UTP; 2 µl of transcription buffer; and 20 U RNase inhibitor with 20 U T7 RNA polymerase for the sense strand or 20 U SP6 RNA polymerase for the antisense strand (DIG RNA labeling kit SP6/T7; Roche, Laval, PQ, Canada). The 440-bp CRP cDNA fragment was similarly treated to produce sense and antisense CRP cRNA probes.
After labeling, the C4 and CRP cRNA probes were treated with 10 U of RNase-free DNase I for 45 minutes at 37°C, ethanol-precipitated, and resuspended in diethyl pyrocarbonate-treated distilled water containing 20 U of RNase inhibitor. The transcripts were analyzed on agarose gels after ethidium bromide staining, and the yields were estimated densitometrically by comparison with a control RNA of known concentration. Immunohistochemical detection of DIG-labeled RNAs on nylon membranes (Hybond-N+; Amersham, Buckinghamshire, UK) revealed equivalent labeling efficiency between sense and antisense cRNAs.
In situ hybridization was performed on paraformaldehyde-fixed, paraffin-embedded blocks of tissue. Seven-micron sections were mounted on silane-coated slides, deparaffinized with xylene, and rehydrated in a graded series of ethanol solutions (100%, 95%, 90%, 85%, 80%, and 70% in diethyl pyrocarbonate-treated distilled water) for 5 minutes at each step and treated with 2 µg/ml of proteinase K (Sigma, Oakville, ON) at 37°C for 1 hour. They were further fixed for 1 hour in 4% paraformaldehyde at 4°C, followed by treatment with 0.25% acetic anhydride in 0.1 mol/L of triethanolamine (pH 8.0). The sections were washed with phosphate-buffered saline before dehydration in a graded series of ethanol as described above for 30 seconds at each step.
The sections were prehybridized for 2 hours at 50°C in a hybridization mixture (50% deionized formamide, 10 mmol/L Tris, pH 7.4, 200 µg/ml yeast tRNA, 1x Denhardt’s solution, 10% dextran sulfate, 600 mmol/L NaCl, 0.25% sodium dodecyl sulfate, and 1 mmol/L ethylenediaminetetraacetic acid). The probes (30 ng/ml) were added to the hybridization mixture, which was heated at 80°C for 10 minutes and cooled before addition to the tissue sections.
Hybridization was performed for 16 hours at 50°C in a humidified chamber. Test sections were hybridized with the antisense cRNA probes, and controls were probed with the sense cRNA probes. After hybridization, the sections were washed twice with 50% deionized formamide in 2x standard saline citrate at 55°C for 30 minutes, followed by incubation with 20 µg/ml RNase A (Sigma Chemical Co., St. Louis, MO) for 30 minutes at 37°C. After washing in 2x standard saline citrate for 20 minutes and then in 0.2x standard saline citrate for 20 minutes twice at 55°C, the sections were incubated in a blocking buffer containing 1.5% blocking reagent (DIG nucleic acid detection kit; Roche), 100 mmol/L Tris, pH 7.5, and 150 mmol/L NaCl overnight at 4°C. Alkaline phosphatase-conjugated anti-DIG antibody (Roche) diluted 1:1,000 in blocking buffer was incubated with sections overnight at 4°C. Before detection of alkaline phosphatase/DIG-labeled RNAs, sections were prewashed in 100 mmol/L Tris, pH 9.5, 100 mmol/L NaCl, and 50 mmol/L MgCl2, and then incubated for 0.5 to 5 hours in the dark at 4°C in color substrates (nitro blue tetrazolium salt and 5-bromo-4-chloro-3-indolyl-phosphate toluidine salt in dimethylformamide) diluted in the prewash buffer as described by the manufacturer. Once the desired color intensity was attained, the color reaction was stopped by washing the sections in 10 mmol/L Tris/1 mmol/L ethylenediaminetetraacetic acid, pH 8.0. The slides were photographed.
Histochemistry and immunohistochemistry were performed on paraffin-embedded, formalin-fixed tissue. Gomori trichrome staining was performed on 7-µm sections mounted on glass slides as previously described.24 Immunohistochemistry for high molecular weight caldesmon using monoclonal antibody (mAb) clone h-CD (1:400, DAKO) was done on slide-mounted 7-µm sections by automated immunostaining (Ventana Immunostainer, Tucson, AZ) after microwave retrieval of the antigen. Slides were counterstained with hematoxylin.
Immunohistochemistry for HLA-DR and C5b-9 was performed as previously described in detail.22-24 Paraffin sections were cut at 18-µm thickness, deparaffinized, and immunostained as free floating sections. HLA-DR was identified using the mAb CR3/43 (1:1000, DAKO)26 and sC5b-9 using a Quidel (San Diego, CA) mAb (1:1000).
Immunostaining for CRP was performed using a rabbit polyclonal antibody (1:20,000; DAKO). Sections were first pretreated with 100% formic acid for 3 minutes and then treated by standard procedures.22-24
The data were analyzed by analysis of variance followed by Student’s t-test. The data were also analyzed by the matched-pair method, comparing in each case plaque tissue, normal artery, and liver. A correction was made in each instance for multiple comparisons using the Holm’s step-down procedure.27 Data were analyzed without correction and also after normalization to the cyclophilin value for the tissue obtained in a parallel amplification. Because of the very small variation in cyclophilin values, the statistical significances were identical. Regression analysis was used to determine whether there was any correlation of the CRP or C4 mRNA level with postmortem delay.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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for CRP,
CD11b, and HLA-DR and as previously published22
for the
complement components, C1q to C9.
Figure 1
shows Polaroid photographs of
ethidium bromide-stained gels demonstrating RT-PCR products for CRP,
CD11b, HLA-DR, and the complement proteins C1q to C9. Figure 1A
shows
that CRP mRNA is produced in heart, liver, kidney, spleen, and normal
artery. There is intense up-regulation in atheromatous plaque material.
Similar results are found for the mRNAs of CD11b (Figure
1B) and
HLA-DR (Figure 1C)
. Polaroid photographs of gels for the mRNAs of C1q
through C9 are shown only for normal artery and atheromatous plaque
material because we have previously reported on the detection of C1q to
C9 mRNAs in heart, liver, spleen, and kidney.22-24
Notice
the more intense bands for all of the complement mRNAs in
atherosclerotic plaque material compared with normal artery.
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shows Western blots in normal
versus plaque material for CRP, CD11b, HLA-DR, and for the
complement proteins. Strong bands were obtained in plaque extracts for
CRP at the expected molecular weight of 28 kd28
(Figure 2A)
, for CD11b at the expected molecular weight of 155
kd29
(Figure 2B)
, and for HLA-DR at the expected molecular
weight of 35 kd30
(Figure 2C)
. Strong bands were also
observed for all of the complement proteins at molecular weights
previously published (Figure 2D)
.22,24
In addition, strong
bands were obtained for the activated complement fragments C4d, C3d,
and C5b-9. These data show that the mRNAs were being translated into
their protein products. They also indicate a sharp up-regulation in
plaques, with full activation of the classical complement pathway,
including formation of the MAC.
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gives quantitative mRNA values
for each of the complement components, CRP, CD11b, HLA-DR, and
cyclophilin. The standard error for cyclophilin values was <0.5%,
indicating that factors related to postmortem delay, underlying
disease, and agonist cause of death had little influence on the values.
Large differences were always observed between values for plaques and
normal arteries, so that the differences were highly significant, with
P values ranging from 0.0003 to 0.0114 (Table 3)
. In
contrast, the standard errors for both normal and plaque tissue were
relatively low, in most cases being <10%. The greatest up-regulation
was for CRP where a 10.2-fold increase of plaque versus
normal artery was observed. Values normalized to cyclophilin were
similarly analyzed, but the corrections were so small that there was no
influence on the significance of the differences.
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, and highly significant increases were obtained
for each of the mRNAs in plaque compared with normal tissue.
Significant increases were also found by paired analyses for the mRNAs
of CRP (P < 0.001) and HLA-DR
(P < 0.02) in plaque tissue compared with liver
although complement and CD11b mRNA levels were similar. Regression
analysis showed no significant correlation of postmortem delay with CRP
mRNA levels in liver (P = 0.57), normal artery
tissue (P = 0.69), or plaque tissue
(P = 0.12). The same was true for C4 mRNA levels
with the respective P values being 0.36, 0.69, and
0.24.
Table 4
gives data for the mRNAs of each
of the complement components, CRP, CD11b, HLA-DR, and cyclophilin for
the various organs. Normal appearing organ tissue was taken in each
case. Again, the data of Table 4
show little variation in cyclophilin
for each organ. They also show that liver had the highest base levels
of all of the components measured, but that the mRNAs were also present
in all organs, indicating local synthesis. However, in none of these
cases was the synthesis of complement components, CRP, HLA-DR, or CD11b
as high as in plaque tissue.
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, show results of
in situ hybridization, as well as histochemical and
immunohistochemical staining of plaque versus normal
arterial tissue. Figure 3
illustrates the cellular makeup of plaque and
normal arterial tissue. Figure 3A
shows a low-power photomicrograph of
a branch of the iliac artery that is trichrome stained. The area
contains a classical plaque where the thickened intima has peeled away
from the media in the shoulder region, leaving an isolated tongue of
the plaque. The fibrous cap shows elongated smooth muscle-derived cells
as well as round and ovoid macrophages, all of which are red stained.
The swollen intima is relatively acellular and contains mostly
green-stained collagen. Figure 3B
is of the area near the peeled
shoulder at higher power, showing many elongated muscle cells and round
or ovoid macrophages, all of which appear as red-stained cells. Figure 3C
is a high-power photomicrograph of caldesmon immunostaining,
identifying the thin elongated cells proliferating in the plaque tissue
to be of smooth muscle as opposed to macrophage origin. Figure 3D
is a
companion high-power photomicrograph showing HLA-DR staining of
macrophages. The cells are quite different in morphology, being round
or ovoid with occasional short processes. Figure 3E
illustrates another
plaque area from a surgically removed endarterectomized carotid artery.
It illustrates a fibrous cap over an acellular swollen intima with the
surrounding areas being highly cellular. Figure 3F
shows a
cross-section of normal aorta. There is no intimal thickening, and no
large deposits of collagen are visible. There is the normal thin
intimal layer and larger fibroelastic medial layer containing elongated
smooth muscle cells.
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shows CRP and C4 in
situ hybridization results of the same area shown in Figure 3B
.
Figure 4A
is a medium-power photomicrograph of in situ
hybridization with the CRP antisense probe. Abundant staining can be
seen in the shoulder area. Figure 4B
shows that no signal is seen using
the CRP sense probe. Figure 4C
shows a high-power photomicrograph,
illustrating the cellular morphology of the hybridizing cells.
Elongated muscle-like cells are positive, as well as round cells with a
macrophage-like morphology similar to the cells shown in Figure 3, C and D
. This indicates that both types of cells are generating CRP.
Figure 4, D–F
, shows comparable in situ data for C4 on
sections nearby to those illustrated in Figure 4, A–C
. Figure 4D
shows
in situ hybridization at medium power using the antisense C4
probe. An intense signal is observed over cells in the shoulder area.
Figure 4E
shows that no signal is obtained using the C4 sense probe.
Figure 4F
is a higher power photomicrograph of the shoulder area
illustrating many positive elongated cells and some round cells,
similar to those hybridizing positively for CRP mRNA. Figure 4, G and H
, shows CRP in situ hybridization of normal aorta using the
antisense (Figure 4G)
and sense (Figure 4H)
probes. The area
corresponds to that shown in Figure 3C
. Only faint signals are picked
up by the antisense probe, whereas no signal is seen with the sense
probe. Figure 4, I and J
, show C4 in situ hybridization of
the same area. Again, a faint signal is picked up with the antisense
probe but none with the sense probe. These results show that normal
smooth-muscle arterial tissue contains low amounts of CRP and
C4 mRNAs in keeping with the RT-PCR results of Figures 1 and 2
and Table 3
.
Figure 5
shows comparisons of in
situ hybridization and immunohistochemistry from the carotid
plaque area shown in Figure 3E
. Figure 5A
shows in situ
hybridization of a shoulder area with the antisense CRP probe. Intense
staining of a patchy nature is visible. Figure 5B
shows in
situ hybridization of the same area in a nearby section using the
C4 antisense probe and there is highly similar staining. Figure 5C
is
another nearby section immunostained for sC5b-9. This illustrates that
activation of the complement pathway has occurred in the same regions
showing up-regulation of CRP and C4 mRNAs. Figure 5D
shows the same
region immunostained for CRP and Figure 5E
for sC5b-9. The
immunostaining is highly similar. This confirms earlier reports of
co-localization of CRP and the MAC13
and extends them by
showing endogenous production of the key components.
Figure 6
shows in situ
hybridization for CRP and C4 in liver sections from a typical case.
Detectable signals with the antisense probes for both CRP and C4 were
observed over hepatocytes, but the signals were considerably weaker
than those from plaque tissue as shown in Figures 4 and 5
. These
findings are consistent with the mRNA data of Tables 3 and 4
,
indicating up-regulation of the mRNAs in plaque tissue but not in
liver. Signals were not detected in vessel leukocytes either in liver
or plaque tissue.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results confirm previous reports of full activation of the classical complement pathway within plaques,33-36 including co-localization of the MAC with CRP.13 Our data support the concept of simple activation of the classical pathway by CRP.13 They are not consistent with mechanisms based only on lipid activation of the alternative pathway .37 CRP is known to activate complement both in vitro11 and in vivo.12 It co-localizes with activated complement in acute myocardial infarction38 as well as plaques. It also appears in association with activated complement in the plaque-associated lesions of Alzheimer’s disease.21 There is evidence that the MAC itself induces CRP deposition,13,39 suggesting a self-perpetuating mechanism. Available anti-inflammatory agents such as NSAIDs might be helpful in interrupting such a cycle, but more appropriate targets for future intervention might be blocking CRP or inhibiting full activation of the complement system. Further studies of the close association of CRP and activated complement, particularly the MAC, in a wide spectrum of chronic inflammatory disorders is clearly warranted.
In our series, the causes of death and postmortem delay varied widely from case to case, but the mRNA values for the various inflammatory markers show that these were noncontributory factors. A point worth noting is the remarkable stability of many mRNAs postmortem, a finding we have previously noted,22,24 and one that has been reported by others.40,41 The levels of cyclophilin mRNA were almost constant in a given tissue regardless of postmortem delay. Furthermore, analysis of CRP mRNA levels in normal arterial tissue, plaque tissue, and liver as a function of postmortem delay showed no correlation. Finally, most cases studied served as their own control because nearby normal arterial tissue was taken in comparison with plaque material. Statistical analysis of these paired samples yielded probability values little different from those obtained by analysis of variance. This is because comparably low values were always observed in normal arterial tissue and comparably high values in atheromatous tissue. The housekeeping gene cyclophilin varied by <1% between all values, whether from normal or atheromatous tissue, so that statistical differences were similar whether raw data or data normalized to cyclophilin values were used.
The increase of mRNAs was accompanied by increases in the protein
products as evidenced by the Western blots of Figure 2
. Thus, the
induction of mRNAs, which is presumably on a sustained basis, is also
reflected in sustained protein production.
The mRNA increase in plaque compared with normal arterial tissue was
somewhat higher for HLA-DR than CD11b (Table 3
, ratio of 3.57
versus 2.34). HLA-DR is expressed on macrophages and
dendritic cells but not on neutrophils. CD11b is expressed on all
phagocytic cells that includes macrophages and neutrophils. It has been
reported that up to 26% of HLA-DR-positive cells in plaque tissue are
desmin-positive42
and that in culture smooth muscle
arterial cells can be induced to express HLA-DR by
-interferon.43
Thus part of our observed HLA-DR
increase could be because of expression on transformed smooth-muscle
cells that could account for the greater increase in HLA-DR compared
with CD11b. However, much of the increase of HLA-DR, as well as CD11b,
presumably reflects the increased number of macrophages in plaque
tissue as shown immunohistochemically (Figure 3)
. CD11b, of course, is
a receptor for complement opsonized targets, so there is a powerful
ligand-receptor interaction in the plaque tissue.
The in situ hybridization and immunohistochemical results confirm the mRNA and Western blot data. They further identify the cell types that are generating the proteins. These are macrophages and endogenous arterial cells that are proliferating predominantly in the deep intimal layer and the fibrous cap. The exact nature of these cells is uncertain. They are characterized by many smooth muscle cell markers,44 as evidenced here by caldesmon.45,46 However, they have clearly been induced to express high levels of proteins such as C4 and CRP. They may relate to the hybrid cell described as a myofibroblast.47 Clearly, further investigation is required to characterize the phenotype of these cells. Suppressing their inflammatory secretions may have potential in retarding evolution of the plaques and subsequent thrombotic events.
Macrophages have previously been reported to generate CRP.48 Macrophages have also been reported to produce all of the classical complement pathway proteins,49 so identification of these cells producing CRP and C4 in plaque tissue is not surprising.
Complement proteins and CRP are known to be produced by hepatocytes, as
confirmed here by the in situ hybridization results of
Figure 6
. The weaker signals from liver compared with plaque tissue are
consistent with the lower levels of the mRNAs. There seemed to be no
significant contribution from circulating leukocytes. Within plaque
tissue, hybridization was not observed over capillaries or other
vessels and mRNA levels were low in the spleen where leukocytes are
concentrated.
We have previously shown high up-regulation of CRP, and activation of the complement system in the absence of antibodies, in Alzheimer’s disease brain tissue,21 ,22 myocardial infarcts,24 and isolated rabbit hearts subjected to reperfusion injury.23 All of these findings relate to the generality of complement up-regulation and activation in certain types of tissue injury, independently of antibodies generated by the adaptive immune system.
After a heart attack or stroke, serum CRP shows dramatic increases. It may be that these increases are primarily because of secretion from injured tissue and not from liver. Lesser amounts may be continuously released from atheromatous tissue. In this event, slight but persistent increases in serum CRP might reflect the atheromatous burden in an apparently healthy individual and thus be a predictor of a subsequent heart attack or stroke. Evidence supporting this concept can be found in a number of epidemiological studies showing that mild increases in serum CRP predict subsequent myocardial infarctions14,32-39,50-55 and peripheral vascular disease.54 They indicate the extent of risk at the time of hospital admission for acute coronary syndromes.56-60 They also predict survival after a heart attack17 or stroke.61 Ridker and colleagues62 in a prospective, nested, case-control study among 28,263 postmenopausal women, found serum CRP to be the strongest predictor of 12 markers tested for subsequent cardiovascular complications, including coronary heart disease, myocardial infarct, and stroke. Taken together, these data suggest that anti-inflammatory therapy may be effective in retarding atherosclerotic plaque development and the vascular complications that follow.
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Acknowledgements |
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Footnotes |
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Supported by grants from the Jack Brown and Family Alzheimer’s Disease Research Fund, as well as donations from Friends of the University of British Columbia and individual British Columbians.
Accepted for publication December 12, 2000.
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P. Singh, M. Hoffmann, R. Wolk, A. S.M. Shamsuzzaman, and V. K. Somers Leptin Induces C-Reactive Protein Expression in Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): e302 - e307. [Abstract] [Full Text] [PDF]
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 S. Norja, L. Nuutila, P. J Karhunen, and S. Goebeler C-reactive protein in vulnerable coronary plaques J. Clin. Pathol., May 1, 2007; 60(5): 545 - 548. [Abstract] [Full Text] [PDF]
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M. Tabuchi, K. Inoue, H. Usui-Kataoka, K. Kobayashi, M. Teramoto, K. Takasugi, K. Shikata, M. Yamamura, K. Ando, K. Nishida, et al. The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis J. Lipid Res., April 1, 2007; 48(4): 768 - 781. [Abstract] [Full Text] [PDF]
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 K. Udvarnoki, L. Cervenak, K. Uray, F. Hudecz, I. Kacskovics, R. Spallek, M. Singh, G. Fust, and Z. Prohaszka Antibodies against C-Reactive Protein Cross-React with 60-Kilodalton Heat Shock Proteins Clin. Vaccine Immunol., April 1, 2007; 14(4): 335 - 341. [Abstract] [Full Text] [PDF]
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 J. Wehner, C. N. Morrell, T. Reynolds, E. R. Rodriguez, and W. M. Baldwin III Antibody and Complement in Transplant Vasculopathy Circ. Res., February 2, 2007; 100(2): 191 - 203. [Abstract] [Full Text] [PDF]
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D. R. Anderson, J. M. Tsutsui, F. Xie, S. J. Radio, and T. R. Porter The role of complement in the adherence of microbubbles to dysfunctional arterial endothelium and atherosclerotic plaque Cardiovasc Res, February 1, 2007; 73(3): 597 - 606. [Abstract] [Full Text] [PDF]
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W. Koenig and N. Khuseyinova Biomarkers of Atherosclerotic Plaque Instability and Rupture Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 15 - 26. [Abstract] [Full Text] [PDF]
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 S.-R. Ji, Y. Wu, L. Zhu, L. A. Potempa, F.-L. Sheng, W. Lu, and J. Zhao Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRPm FASEB J, January 1, 2007; 21(1): 284 - 294. [Abstract] [Full Text] [PDF]
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 M.-L. Gross, H.-P. Meyer, H. Ziebart, P. Rieger, U. Wenzel, K. Amann, I. Berger, M. Adamczak, P. Schirmacher, and E. Ritz Calcification of Coronary Intima and Media: Immunohistochemistry, Backscatter Imaging, and X-Ray Analysis in Renal and Nonrenal Patients Clin. J. Am. Soc. Nephrol., January 1, 2007; 2(1): 121 - 134. [Abstract] [Full Text] [PDF]
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F. Blaschke, Y. Takata, E. Caglayan, A. Collins, P. Tontonoz, W. A. Hsueh, and R. K. Tangirala A Nuclear Receptor Corepressor-Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor Circ. Res., December 8, 2006; 99(12): e88 - e99. [Abstract] [Full Text] [PDF]
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S. Devaraj, B. Davis, S. I. Simon, and I. Jialal CRP promotes monocyte-endothelial cell adhesion via Fc{gamma} receptors in human aortic endothelial cells under static and shear flow conditions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1170 - H1176. [Abstract] [Full Text] [PDF]
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 R. Somani, P. J. Grant, K. Kain, A. J. Catto, and A. M. Carter Complement C3 and C-Reactive Protein Are Elevated in South Asians Independent of a Family History of Stroke Stroke, August 1, 2006; 37(8): 2001 - 2006. [Abstract] [Full Text] [PDF]
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E. Paffen and M. P.M. deMaat C-reactive protein in atherosclerosis: A causal factor? Cardiovasc Res, July 1, 2006; 71(1): 30 - 39. [Abstract] [Full Text] [PDF]
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 B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, I. Jialal, B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, and I. Jialal The Verdict Is Still Out Circulation, May 2, 2006; 113(17): 2128 - 2151. [Full Text] [PDF]
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J. Krupinski, M. M. Turu, J. Martinez-Gonzalez, A. Carvajal, J. O. Juan-Babot, E. Iborra, M. Slevin, F. Rubio, and L. Badimon Endogenous Expression of C-Reactive Protein Is Increased in Active (Ulcerated Noncomplicated) Human Carotid Artery Plaques Stroke, May 1, 2006; 37(5): 1200 - 1204. [Abstract] [Full Text] [PDF]
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 I. Montero, J. Orbe, N. Varo, O. Beloqui, J. I. Monreal, J. A. Rodriguez, J. Diez, P. Libby, and J. A. Paramo C-Reactive Protein Induces Matrix Metalloproteinase-1 and -10 in Human Endothelial Cells: Implications for Clinical and Subclinical Atherosclerosis J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1369 - 1378. [Abstract] [Full Text] [PDF]
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I. Jialal, S. Devaraj, and U. Singh C-Reactive Protein and the Vascular Endothelium: Implications for Plaque Instability J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1379 - 1381. [Full Text] [PDF]
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S.-R. Ji, Y. Wu, L. A. Potempa, Y.-H. Liang, and J. Zhao Effect of Modified C-Reactive Protein on Complement Activation: A Possible Complement Regulatory Role of Modified or Monomeric C-Reactive Protein in Atherosclerotic Lesions Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 935 - 941. [Abstract] [Full Text] [PDF]
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 D Skowasch, S Schrempf, C J Preusse, J A Likungu, A Welz, B Luderitz, and G Bauriedel Tissue resident C reactive protein in degenerative aortic valves: correlation with serum C reactive protein concentrations and modification by statins Heart, April 1, 2006; 92(4): 495 - 498. [Abstract] [Full Text] [PDF]
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 I. Jialal, S. Devaraj, U. Singh, J. Fan, and Y. E. Chen Sources of CRP in Atherosclerotic Lesions Am. J. Pathol., March 1, 2006; 168(3): 1054 - 1056. [Full Text] [PDF]
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M Meuwissen, A C van der Wal, H W M Niessen, K T Koch, R J de Winter, C M van der Loos, S Z H Rittersma, S A J Chamuleau, J G P Tijssen, A E Becker, et al. Colocalisation of intraplaque C reactive protein, complement, oxidised low density lipoprotein, and macrophages in stable and unstable angina and acute myocardial infarction J. Clin. Pathol., February 1, 2006; 59(2): 196 - 201. [Abstract] [Full Text] [PDF]
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 D.-H. Kang, S.-K. Park, I.-K. Lee, and R. J. Johnson Uric Acid-Induced C-Reactive Protein Expression: Implication on Cell Proliferation and Nitric Oxide Production of Human Vascular Cells J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3553 - 3562. [Abstract] [Full Text] [PDF]
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 S G Baidya and Q-T Zeng Helper T cells and atherosclerosis: the cytokine web Postgrad. Med. J., December 1, 2005; 81(962): 746 - 752. [Abstract] [Full Text] [PDF]
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 I. Ciubotaru, L. A. Potempa, and R. C. Wander Production of Modified C-Reactive Protein in U937-Derived Macrophages Experimental Biology and Medicine, November 1, 2005; 230(10): 762 - 770. [Abstract] [Full Text] [PDF]
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W. S. Speidl, M. Exner, J. Amighi, S. P. Kastl, G. Zorn, G. Maurer, O. Wagner, K. Huber, E. Minar, J. Wojta, et al. Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis Eur. Heart J., November 1, 2005; 26(21): 2294 - 2299. [Abstract] [Full Text] [PDF]
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 A. M Carter Inflammation, thrombosis and acute coronary syndromes Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 113 - 121. [Abstract] [PDF]
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J. Torzewski C-Reactive Protein and Atherogenesis: New Insights from Established Animal Models Am. J. Pathol., October 1, 2005; 167(4): 923 - 925. [Full Text] [PDF]
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H. Sun, T. Koike, T. Ichikawa, K. Hatakeyama, M. Shiomi, B. Zhang, S. Kitajima, M. Morimoto, T. Watanabe, Y. Asada, et al. C-Reactive Protein in Atherosclerotic Lesions: Its Origin and Pathophysiological Significance Am. J. Pathol., October 1, 2005; 167(4): 1139 - 1148. [Abstract] [Full Text] [PDF]
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U. Singh, S. Devaraj, and I. Jialal C-Reactive Protein Decreases Tissue Plasminogen Activator Activity in Human Aortic Endothelial Cells: Evidence that C-Reactive Protein Is a Procoagulant Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2216 - 2221. [Abstract] [Full Text] [PDF]
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E. T.H. Yeh A New Perspective on the Biology of C-Reactive Protein Circ. Res., September 30, 2005; 97(7): 609 - 611. [Full Text] [PDF]
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S. B. Schwedler, K. Amann, K. Wernicke, A. Krebs, M. Nauck, C. Wanner, L. A. Potempa, and J. Galle Native C-Reactive Protein Increases Whereas Modified C-Reactive Protein Reduces Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, August 16, 2005; 112(7): 1016 - 1023. [Abstract] [Full Text] [PDF]
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A. Trion, M.P.M. de Maat, J.W. Jukema, A. van der Laarse, M.C. Maas, E.H. Offerman, L.M. Havekes, A.J. Szalai, H.M.G. Princen, and J.J. Emeis No Effect of C-Reactive Protein on Early Atherosclerosis Development in Apolipoprotein E*3-Leiden/Human C-Reactive Protein Transgenic Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1635 - 1640. [Abstract] [Full Text] [PDF]
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T. Inoue, T. Kato, T. Uchida, M. Sakuma, A. Nakajima, M. Shibazaki, Y. Imoto, M. Saito, S. Hashimoto, Y. Hikichi, et al. Local Release of C-Reactive Protein From Vulnerable Plaque or Coronary Arterial Wall Injured by Stenting J. Am. Coll. Cardiol., July 19, 2005; 46(2): 239 - 245. [Abstract] [Full Text] [PDF]
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Y Sato, K Hatakeyama, A Yamashita, K Marutsuka, A Sumiyoshi, and Y Asada Proportion of fibrin and platelets differs in thrombi on ruptured and eroded coronary atherosclerotic plaques in humans Heart, April 1, 2005; 91(4): 526 - 530. [Abstract] [Full Text] [PDF]
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L. van Tits, J. de Graaf, H. Toenhake, W. van Heerde, and A. Stalenhoef C-Reactive Protein and Annexin A5 Bind to Distinct Sites of Negatively Charged Phospholipids Present in Oxidized Low-Density Lipoprotein Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 717 - 722. [Abstract] [Full Text] [PDF]
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S. K. Venugopal, S. Devaraj, and I. Jialal Macrophage Conditioned Medium Induces the Expression of C-Reactive Protein in Human Aortic Endothelial Cells: Potential for Paracrine/Autocrine Effects Am. J. Pathol., April 1, 2005; 166(4): 1265 - 1271. [Abstract] [Full Text] [PDF]
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W. Maier, L. A. Altwegg, R. Corti, S. Gay, M. Hersberger, F. E. Maly, G. Sutsch, M. Roffi, M. Neidhart, F. R. Eberli, et al. Inflammatory Markers at the Site of Ruptured Plaque in Acute Myocardial Infarction: Locally Increased Interleukin-6 and Serum Amyloid A but Decreased C-Reactive Protein Circulation, March 22, 2005; 111(11): 1355 - 1361. [Abstract] [Full Text] [PDF]
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 T. C. Register, J. A. Cann, J. R. Kaplan, J. K. Williams, M. R. Adams, T. M. Morgan, M. S. Anthony, R. M. Blair, J. D. Wagner, and T. B. Clarkson Effects of Soy Isoflavones and Conjugated Equine Estrogens on Inflammatory Markers in Atherosclerotic, Ovariectomized Monkeys J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1734 - 1740. [Abstract] [Full Text] [PDF]
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 I. J. Chang and R. C. Harris Are All COX-2 Inhibitors Created Equal? Hypertension, February 1, 2005; 45(2): 178 - 180. [Full Text] [PDF]
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Y. Ivashchenko, F. Kramer, S. Schafer, A. Bucher, K. Veit, V. Hombach, A. Busch, O. Ritzeler, J. Dedio, and J. Torzewski Protein Kinase C Pathway Is Involved in Transcriptional Regulation of C-Reactive Protein Synthesis in Human Hepatocytes Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 186 - 192. [Abstract] [Full Text] [PDF]
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F. Blaschke, D. Bruemmer, F. Yin, Y. Takata, W. Wang, M. C. Fishbein, T. Okura, J. Higaki, K. Graf, E. Fleck, et al. C-Reactive Protein Induces Apoptosis in Human Coronary Vascular Smooth Muscle Cells Circulation, August 3, 2004; 110(5): 579 - 587. [Abstract] [Full Text] [PDF]
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 H. ALHO, P. SILLANAUKEE, A. KALELA, O. JAAKKOLA, S. LAINE, and S. T. NIKKARI ALCOHOL MISUSE INCREASES SERUM ANTIBODIES TO OXIDIZED LDL AND C-REACTIVE PROTEIN Alcohol Alcohol., July 1, 2004; 39(4): 312 - 315. [Abstract] [Full Text] [PDF]
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I. Jialal, S. Devaraj, and S. K. Venugopal C-Reactive Protein: Risk Marker or Mediator in Atherothrombosis? Hypertension, July 1, 2004; 44(1): 6 - 11. [Abstract] [Full Text] [PDF]
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S.-H. Li, P. E. Szmitko, R. D. Weisel, C.-H. Wang, P. W.M. Fedak, R.-K. Li, D. A.G. Mickle, and S. Verma C-Reactive Protein Upregulates Complement-Inhibitory Factors in Endothelial Cells Circulation, February 24, 2004; 109(7): 833 - 836. [Abstract] [Full Text] [PDF]
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A. Paul, K. W.S. Ko, L. Li, V. Yechoor, M. A. McCrory, A. J. Szalai, and L. Chan C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, February 10, 2004; 109(5): 647 - 655. [Abstract] [Full Text] [PDF]
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T. N. Williams, C. X. Zhang, B. A. Game, L. He, and Y. Huang C-Reactive Protein Stimulates MMP-1 Expression in U937 Histiocytes Through Fc{gamma}RII and Extracellular Signal-Regulated Kinase Pathway:: An Implication of CRP Involvement in Plaque Destabilization Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 61 - 66. [Abstract] [Full Text] [PDF]
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 G Vaudo, S Marchesi, R Gerli, R Allegrucci, A Giordano, D Siepi, M Pirro, Y Shoenfeld, G Schillaci, and E Mannarino Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activity Ann Rheum Dis, January 1, 2004; 63(1): 31 - 35. [Abstract] [Full Text] [PDF]
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 G.M. Hirschfield and M.B. Pepys C-reactive protein and cardiovascular disease: new insights from an old molecule QJM, November 1, 2003; 96(11): 793 - 807. [Abstract] [Full Text] [PDF]
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 G. J. Blake and P. M. Ridker C-reactive protein: a surrogate risk marker or mediator of atherothrombosis? Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1250 - R1252. [Full Text] [PDF]
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P. Calabro, J. T. Willerson, and E. T.H. Yeh Inflammatory Cytokines Stimulated C-Reactive Protein Production by Human Coronary Artery Smooth Muscle Cells Circulation, October 21, 2003; 108(16): 1930 - 1932. [Abstract] [Full Text] [PDF]
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W. J. Jabs, E. Theissing, M. Nitschke, J.F. M. Bechtel, M. Duchrow, S. Mohamed, B. Jahrbeck, H.-H. Sievers, J. Steinhoff, and C. Bartels Local Generation of C-Reactive Protein in Diseased Coronary Artery Venous Bypass Grafts and Normal Vascular Tissue Circulation, September 23, 2003; 108(12): 1428 - 1431. [Abstract] [Full Text] [PDF]
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 J. R. Turk, J. A. Carroll, M. H. Laughlin, T. R. Thomas, J. Casati, D. K. Bowles, and M. Sturek C-reactive protein correlates with macrophage accumulation in coronary arteries of hypercholesterolemic pigs J Appl Physiol, September 1, 2003; 95(3): 1301 - 1304. [Abstract] [Full Text] [PDF]
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S. Kobayashi, N. Inoue, Y. Ohashi, M. Terashima, K. Matsui, T. Mori, H. Fujita, K. Awano, K. Kobayashi, H. Azumi, et al. Interaction of Oxidative Stress and Inflammatory Response in Coronary Plaque Instability: Important Role of C-Reactive Protein Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1398 - 1404. [Abstract] [Full Text] [PDF]
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R. Oksjoki, H. Jarva, P. T. Kovanen, P. Laine, S. Meri, and M. O. Pentikainen Association Between Complement Factor H and Proteoglycans in Early Human Coronary Atherosclerotic Lesions: Implications for Local Regulation of Complement Activation Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 630 - 636. [Abstract] [Full Text] [PDF]
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T. Vainas, T. Lubbers, F. R.M. Stassen, S. B. Herngreen, M. P. van Dieijen-Visser, C. A. Bruggeman, P. J.E.H.M. Kitslaar, and G. W. H. Schurink Serum C-Reactive Protein Level Is Associated With Abdominal Aortic Aneurysm Size and May Be Produced by Aneurysmal Tissue Circulation, March 4, 2003; 107(8): 1103 - 1105. [Abstract] [Full Text] [PDF]
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G. J. Blake and P. M. Ridker C-reactive protein and other inflammatory risk markers in acute coronary syndromes J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 37S - 42S. [Abstract] [Full Text] [PDF]
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 M. A. Zimmerman, C. H. Selzman, C. Cothren, A. C. Sorensen, C. D. Raeburn, and A. H. Harken Diagnostic Implications of C-Reactive Protein Arch Surg, February 1, 2003; 138(2): 220 - 224. [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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 D. L. Bhatt, E. J. Topol, I. Kushner, and A. Sehgal The Arterial Inflammation Hypothesis Arch Intern Med, October 28, 2002; 162(19): 2249 - 2251. [Full Text] [PDF]
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J. C. Mason, Z. Ahmed, R. Mankoff, E. A. Lidington, S. Ahmad, V. Bhatia, A. Kinderlerer, A. M. Randi, and D. O. Haskard Statin-Induced Expression of Decay-Accelerating Factor Protects Vascular Endothelium Against Complement-Mediated Injury Circ. Res., October 18, 2002; 91(8): 696 - 703. [Abstract] [Full Text] [PDF]
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 S. Nakashima, Z. Qian, S. Rahimi, B. A. Wasowska, and W. M. Baldwin III Membrane Attack Complex Contributes to Destruction of Vascular Integrity in Acute Lung Allograft Rejection J. Immunol., October 15, 2002; 169(8): 4620 - 4627. [Abstract] [Full Text] [PDF]
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G. J. Blake and P. M. Ridker C-Reactive Protein, Subclinical Atherosclerosis, and Risk of Cardiovascular Events Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1512 - 1513. [Full Text] [PDF]
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 P. L. McGeer and E. G. McGeer Innate Immunity, Local Inflammation, and Degenerative Disease Sci. Aging Knowl. Environ., July 24, 2002; 2002(29): re3 - 3. [Abstract] [Full Text] [PDF]
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D. L. Bhatt and E. J. Topol Need to Test the Arterial Inflammation Hypothesis Circulation, July 2, 2002; 106(1): 136 - 140. [Full Text] [PDF]
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C. Buono, C. E. Come, J. L. Witztum, G. F. Maguire, P. W. Connelly, M. Carroll, and A. H. Lichtman Influence of C3 Deficiency on Atherosclerosis Circulation, June 25, 2002; 105(25): 3025 - 3031. [Abstract] [Full Text] [PDF]
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 T. G. Burnakis, M. Fleming, M. A. Konstam, L. A. Demopoulos, K. D. Grant, E. J. Haldey, M. Pappagallo, M. Minic, P. L. McGeer, E. G. McGeer, et al. Cardiovascular Events and COX-2 Inhibitors JAMA, December 12, 2001; 286(22): 2808 - 2813. [Full Text] [PDF]
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G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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K. Yasojima, C. Schwab, E. G. McGeer, and P. L. McGeer Complement Components, but Not Complement Inhibitors, Are Upregulated in Atherosclerotic Plaques Arterioscler. Thromb. Vasc. Biol., July 1, 2001; 21(7): 1214 - 1219. [Abstract] [Full Text] [PDF]
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 J. C. Mason, E. A. Lidington, S. R. Ahmad, and D. O. Haskard bFGF and VEGF synergistically enhance endothelial cytoprotection via decay-accelerating factor induction Am J Physiol Cell Physiol, March 1, 2002; 282(3): C578 - C587. [Abstract] [Full Text] [PDF]
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K. K. Koh, W. H. Schenke, M. A. Waclawiw, G. Csako, and R. O. Cannon III Statin Attenuates Increase in C-Reactive Protein During Estrogen Replacement Therapy in Postmenopausal Women Circulation, April 2, 2002; 105(13): 1531 - 1533. [Abstract] [Full Text] [PDF]
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A. P. Burke, R. P. Tracy, F. Kolodgie, G. T. Malcom, A. Zieske, R. Kutys, J. Pestaner, J. Smialek, and R. Virmani Elevated C-Reactive Protein Values and Atherosclerosis in Sudden Coronary Death: Association With Different Pathologies Circulation, April 30, 2002; 105(17): 2019 - 2023. [Abstract] [Full Text] [PDF]
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