(Circulation. 1999;100:614-620.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Enhanced Levels of Soluble and Membrane-Bound CD40 Ligand in Patients With Unstable Angina
Possible Reflection of T Lymphocyte and Platelet Involvement in the Pathogenesis of Acute Coronary Syndromes
From the Section of Clinical Immunology and Infectious Diseases (P.A., F.M., S.S.F.), Research Institute for Internal Medicine (P.A., F.M., N.O.S., S.S.F.), Section of Endocrinology, Medical Department (T.U.), and Department of Cardiology, Division of Heart and Lung Diseases (T.B., E.A., A.B., K.F., L.G.), University of Oslo, Rikshospitalet, Oslo, Norway.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Background—The CD40 ligand (CD40L) on activated T cells and platelets may be activating matrix metalloproteinases, inducing procoagulant activity, and be involved in the pathogenesis of acute coronary syndromes by promoting plaque rupture in atheroma.
Methods and Results—To study the role of CD40L-CD40 interaction in coronary disease, we analyzed levels of soluble (s) and membrane-bound CD40L in the peripheral blood from 29 patients with stable angina, 26 with unstable angina, and 19 controls. Our main findings follow. (1) Patients with unstable angina had significantly raised serum levels of sCD40L when compared with patients with stable angina and controls. (2) Platelets could release large amounts of sCD40L when stimulated ex vivo with the thrombin receptor–agonist peptide SFLLRN in both patients and controls. (3) Platelets in patients with unstable angina were characterized ex vivo by decreased intracellular levels and decreased SFLLRN-stimulated release of sCD40L, which may possibly represent a higher percentage of degranulated platelets in these patients. (4) T cells in patients with unstable angina had enhanced surface expression of CD40L and increased release of sCD40L on anti-CD3/anti-CD28 stimulation in vitro when compared with patients with stable angina and controls. (5) Recombinant CD40L and serum from patients with unstable angina who had high sCD40L levels induced enhanced release of monocyte chemoattractant peptide-1 from mononuclear cells, a CC-chemokine involved in the pathogenesis of atherosclerosis.
Conclusions—This first demonstration of enhanced levels of soluble and membrane-bound forms of CD40L in angina patients, with particularly high levels in patients with unstable angina, suggests that CD40L-CD40 interaction may play a pathogenic role in both the long-term atherosclerotic process and in the triggering and propagation of acute coronary syndromes.
Key Words: angina • platelets • T cells • immunology • CD40 • atherosclerosis
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Increasing evidence shows that inflammatory and immunologic mediators may play a role in the pathogenesis of atherosclerosis and coronary artery disease. Elevated circulating levels of inflammatory substances, such as inflammatory cytokines and adhesion molecules, are found in patients with angina, particularly in those with unstable disease.1 2 Also, activated monocytes, T cells, and granulocytes occur in patients with unstable angina; enhanced activation occurs in cells isolated from the coronary sinus.3 4 Moreover, extensive infiltration of blood-derived macrophages and T cells into the vessel wall seems to be an important feature of the active stages of atherosclerosis.5 6
The rupture of lipid-rich coronary plaques, with subsequent
thrombosis, is an important mechanism underlying the sudden onset of
acute coronary syndromes, and degradation of the connective
tissue matrix protein by activated matrix metalloproteinases
(MMPs) within the atherosclerotic plaque may play a major role in this
process.7 Notably, inflammatory mediators, such as tumor
necrosis factor-
(TNF) and interleukin-1, upregulate MMP activity
in macrophages,8 and this interaction may
represent a pathogenic link between persistent immune
activation and the development of plaque rupture.
CD40 ligand (CD40L), a transmembrane protein structurally related to
TNF, was originally identified on
CD4+ T cells, but it was recently found also on
activated platelets.9 10 11 Both membrane-bound
and soluble (s) forms of this ligand may interact with CD40, which is
constitutively expressed on B cells, macrophages,
endothelial cells, and vascular smooth muscle cells
(SMCs), resulting in various inflammatory
responses.9 10 12 Thus, some have suggested that
CD40L-CD40 interaction plays a pathogenic role in inflammatory
disorders such as autoimmune diseases, multiple sclerosis, and cardiac
allograft rejection.10 12 Recently, Mach et
al13 reported the presence of T cells expressing CD40L
within atherosclerotic plaques in humans. Also, both membrane-bound and
soluble CD40L may promote MMP expression in vascular SMCs and
macrophages and induce procoagulant activity in monocytes and
the endothelium.14 15 16 Thus, it is
tempting to hypothesize that CD40L-CD40 interaction may contribute to
the development of atherosclerosis and, by
representing a new pathway of destabilization in human
atheroma, also to the triggering of acute coronary
events. To further elucidate the possible role of CD40L-CD40
interaction in coronary disease, we analyzed the levels
of membrane-bound and soluble CD40L in peripheral blood
from patients with stable and unstable angina; we particularly focused
on the potential role of T cells and platelets.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Patients and Controls
Between January and June of 1998, patients undergoing clinically indicated diagnostic coronary angiography in our coronary care unit were consecutively registered. Among those fulfilling the criteria for unstable angina (see below), 26 patients were selected randomly for participation in the study (Table
). All patients with
unstable angina had experienced ischemic chest pain at rest
within the preceding 48 hours (ie, Braunwald's class
IIIB17 ), but they had no evidence of myocardial necrosis
by enzymatic criteria. Transient ST-T segment depression and/or T-wave
inversion were present in all cases. For comparison, 29 sex- and
age-matched patients with stable angina were randomly selected among
those presenting to our department in the same period for
diagnostic coronary angiography or
percutaneous coronary angioplasty (PTCA). All
these patients had long-term, stable, effort angina that had
lasted at least 6 months and had a positive exercise test. The
exclusion criteria in the study included a myocardial infarction within
the previous month, the presence of any ECG abnormalities invalidating
ST-segment analyses, elevated serum levels of cardiac-related
enzymes, thrombolytic therapy in the previous month, or
body temperature >38.0°C. Furthermore, all patients with suspected
or proven long-term or intercurrent inflammatory disease likely to be
associated with short-term phase response (ie, patients with
infection, malignancies, autoimmune disorders, diabetes mellitus, and
pulmonary disease) and patients with liver or kidney disease
were also excluded. Coronary angiography was performed by
standard techniques within 2 days after admission, and the diagnosis of
coronary artery disease was confirmed by at least 1 diseased
vessel (>75% narrowing of luminal diameter) in all patients.
Controls in the study were 19 sex- and age-matched healthy blood donors
and health care workers (14 men and 5 women aged 53±15 years).
Informed consent for participation in the study was obtained from all
individuals.
|
Blood Sampling Protocol
Peripheral venous blood was drawn into pyrogen-free
blood collection tubes without any additives (Becton Dickinson),
immediately immersed in melting ice, and allowed to clot for 1 hour
before centrifugation (1500g and 4°C for
10 minutes). Serum was stored at -80°C until analyzed, and
samples were thawed only once.
Release of sCD40L from Platelets in Platelet-Rich
Plasma
Preparation and stimulation of platelet-rich plasma (PRP)
was performed as previously described.18 Briefly, a volume
of 475 µL of PRP was incubated by gentle tilting for 30 minutes at
room temperature after the addition of 25 µL of the thrombin
receptor–agonist peptide SFLLRN (Biotechnology Center of Oslo,
Norway; final concentration, 100 µmol/L) or Tris-buffered saline
only (unstimulated sample). At baseline and after 30 minutes, equal
volumes of PRP were centrifuged at 11,000g and 4°C
for 10 minutes, and platelet-free supernatant and a platelet
pellet with 500 µL of Tris-buffered saline were stored separately at
-80°C. The platelet pellets were lysed by freezing and thawing 3
times, and the concentration of sCD40L was analyzed in the
lysates. The increase in sCD40L levels (nanograms per
108 platelets) in supernatants from
unstimulated and SFLLRN-stimulated PRP was expressed as the
concentration in the supernatant at the end of the experiment minus the
concentration in the supernatant at baseline.
Isolation of Cells
Peripheral blood mononuclear cells (PBMCs) were
obtained from heparinized blood by Isopaque-Ficoll (Lymphoprep, Nycomed
Pharma AS) gradient centrifugation within 45 minutes.
Negative selection of CD3+ T cells from PBMCs was
performed by monodisperse immunomagnetic beads as previously
described.19 The negatively selected T cells consisted of
>90% CD3+ cells (flow cytometry).
Stimulation of Cells
For examining the release of sCD40L from
CD3+ T cells (106 cells/mL;
200 µL/well), cells were incubated in flat-bottomed, 96-well
microtiter trays (Costar) in serum-free medium alone (X-vivo 15;
BioWhittaker) or with stimulants (anti-CD3 mAb [final concentration,
1.2 ng/mL; clone SpvT3b] combined with anti-CD28
mAb [final concentration, 50 ng/mL; clone 15E8 {402}; from CLB]
and monodisperse immunomagnetic beads coated with sheep anti-mouse IgG
[Dynal] at a cell-to-bead ratio of 1:1 [cross-linking]). For
examining the biological effects of human sCD40L, PBMCs
(106 cells/mL; 200 µL/well; Costar) were
incubated in serum-free medium alone (X-vivo 15) or stimulated with
trimeric human CD40 ligand/leucine zipper fusion protein (Immunex Corp,
Seattle, Wash) or pooled serum from angina patients or controls; the
pooled serum was processed as previously described.20
After 48 hours, cell-free supernatants were harvested and
analyzed for levels of macrophage chemoattractant
protein-1 (MCP-1) by enzyme immunoassay (EIA; R&D Systems). In some
experiments, monoclonal mouse antibodies against human CD40L (clone
M90, Immunex Corp; final concentration, 50 µg/mL) or control mouse
IgG1 (final concentration, 50 µg/mL; R&D
Systems) were also added to cell cultures.
Detection of Membrane-Bound CD40L on T-Cell Subsets by Flow
Cytometry
Peripheral venous blood was drawn into sterile tubes
containing EDTA (Becton Dickinson). Within 1 hour, 300 µL of
whole blood was mixed with 5 to 20 µL of the appropriate monoclonal
antibody conjugates for 30 minutes (4°C in darkness). The following
antibodies were used for staining: anti-CD3 (clone SK7) phycoerythrin,
anti-CD4 (clone SK3) and anti-CD8 (clone SK1) peridin chlorophyll
protein (all from Becton Dickinson), and anti-CD40L (clone 24 to 31)
fluorescein isothiocyanate (Ancell Corp). Isotype-matched
fluorescein isothiocyanate– and phycoerythrin-conjugated
mouse IgG (Pharmigen) were used as negative controls. After incubation,
each sample was treated with 2 mL of a lysing solution of
fluorescence-activated cell sorter (Becton
Dickinson), washed once with cold PBS, resuspended in PBS with 1%
paraformaldehyde, and stored at 4°C before
examination in a fluorescence-activated cell sorter
scanning flow cytometer (Becton Dickinson) within 24 hours. A total of
10 000 cells were acquired and analyzed by CellQuest software
(Becton Dickinson). The boundaries between stained and unstained
populations were set using the isotype control settings, such that
<1% of the events in the control tube were scored as positive.
Detection of sCD40L by EIA
Levels of sCD40L were determined by EIA (detection limit, 0.095
ng/mL; Bender Medsystems) according to the manufacturer's
instructions.
Statistical Analysis
When comparing 3 groups of individuals, 1-way ANOVA was followed
by Scheffe's post hoc test for statistical significance. The CD40L
data were not normally distributed, and the data were, therefore,
subjected to logarithmic transformation before performing the ANOVA
analysis. For comparisons within the same individuals over
time, the Wilcoxon matched pairs test was used. The
calculations were performed using the Statistical Package for Social
Sciences (SPSS, version 7.5) software package. If not otherwise stated,
data are given as medians and 25th to 75th percentiles.
P<0.05 (2-sided) was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Serum Levels of sCD40L
Both patients with stable and unstable angina showed raised levels of sCD40L compared with controls; particularly high levels occurred in patients with unstable disease (Figure 1A
). In 5 patients with unstable angina,
blood samples were also available from a time before the development of
the unstable disease (median time between blood samplings, 10 weeks;
range, 4 to 15 weeks). Notably, all these patients had a rise in sCD40L
levels concomitant with the development of unstable angina (Figure 1B). Furthermore, serum levels of sCD40L were analyzed
in 5 patients with stable angina before and 16 hours after PTCA and, as
can be seen in Figure 1C, PTCA induced a marked rise in sCD40L
levels in all patients.
|
Medications used by angina patients may influence the serum level of
sCD40L. However, we found no association between the concentration of
sCD40L and the use of the actual medication (Table
), including
drugs with known effects on platelet function (ie, aspirin).
Furthermore, no associations were found between sCD40L levels and sex,
smoking status, or lipid status in patients with either stable or
unstable angina (data not shown).
Release of sCD40L from Unstimulated and SFLLRN-Stimulated
PRP
Henn et al11 recently demonstrated that
activated platelets express CD40L on their surface. We,
therefore, examined whether (1) activated platelets could
release sCD40L extracellularly and (2) any difference existed in the
release of sCD40L between patients and control subjects. This was
studied in 9 patients with unstable angina, 9 with stable angina, and
13 controls. As shown in Figure 2, the
platelets provided large amounts of sCD40L after lysis and released
large amounts of sCD40L into the supernatant on SFLLRN stimulation in
both patients and controls. However, platelets from patients with
unstable angina had markedly decreased intracellular sCD40L levels and
decreased SFLLRN-stimulated release of this ligand when compared with
both controls and patients with stable angina (Figure 2). As for
the spontaneous release of sCD40L from platelets (30 minutes of
incubation of PRP), the levels were low in both patients and controls
(
1/50 of levels after SFLLRN stimulation), but raised concentrations
existed in patients with unstable angina when compared with controls
and patients with stable angina (data not shown).
|
CD40L in CD4+ and CD8+ T Cells
Activated T cells express membrane-bound
CD40L.10 Therefore, we examined the expression of CD40L in
CD4+ and CD8+ T cells by
flow cytometry in the same individuals in whom sCD40L in PRP had been
studied. Although no differences existed in the percentage of
CD4+ or CD8+ T cells out of
the total numbers of lymphocytes when comparing patients with both
kinds of angina and controls (data not shown), patients with unstable
disease had a higher percentage of both CD4+ and
CD8+ cells expressing CD40L compared with the 2
other groups of individuals (Figure 3).
Compared with controls, patients with stable angina also had an
increased percentage of CD8+, but not
CD4+, T cells expressing CD40L (Figure 3).
|
In a separate experiment, we examined whether T cells from patients
with unstable (n=5) and stable (n=5) angina and healthy controls (n=5)
could release sCD40L on activation. Interestingly, T cells stimulated
with anti-CD3/anti-CD28 released considerable amounts of sCD40L into
the supernatant in both controls and angina patients, with the highest
levels in patients with unstable disease (Figure 4).
|
Biological Effects of sCD40L
Several studies suggest that CD40L in its soluble form may elicit
biological activity, eg, enhanced MMP synthesis, in vascular
SMCs.14 To further elucidate the possible effects of
raised sCD40L levels in patients with unstable angina, additional
experiments were performed using PBMCs from 4 healthy controls. MCP-1
seems to play a pathogenic role in
atherosclerosis,21 and we hypothesized
that sCD40L, known as a potent monocyte
activator,22 would enhance MCP-1
production in these cells. As shown in Figure 5, sCD40L (given as trimeric human
CD40L/leucine zipper fusion protein) induced a dose-dependent and
specific increase in the release of MCP-1 from PBMCs. Also, pooled
serum from the 4 patients with unstable angina who had the highest
sCD40L levels (mean, 8.1 ng/mL), but not pooled serum from the 4
healthy controls (mean sCD40L levels, 0.9 ng/mL), induced an increase
in MCP-1 release from PBMCs, and this increase was partly blocked by an
inhibitory monoclonal antibody for CD40L (Figure 5).
At a concentration of the CD40L fusion protein comparable to the sCD40L
level in pooled serum from patients with unstable angina, no
MCP-1-inducing effects were seen, probably reflecting the fact that
other inflammatory mediators present in serum from patients with
unstable angina may potentiate the stimulatory effect of
sCD40L.23
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The present study shows, for the first time, signs of abnormal CD40L-CD40 interaction in patients with unstable angina; these patients had significantly higher levels of sCD40L compared with both controls and patients with stable angina. The patients with unstable angina were also characterized by enhanced expression of membrane-bound CD40L on both CD4+ and CD8+ T cells. Finally, although endothelial cells, vascular SMCs, tissue-derived macrophages, and B cells may be involved,13 24 our findings suggest that T cells and, particularly, platelets are major contributors to the elevated serum levels of sCD40L in patients with unstable angina.
Both soluble and, in particular, membrane-bound CD40L may have biological effects on a number of cell types,10 11 22 and the increased CD40L levels in patients with unstable angina may reflect important pathogenic aspects in these patients. The rupture of an atherosclerotic plaque, which again triggers thrombosis, is an important pathogenic event in the development of acute coronary syndromes,5 7 and enhanced CD40L-CD40 interaction may be involved in this process. The MMP-enzyme family probably plays a crucial role in undermining the integrity of the tissue in an atherosclerotic plaque, which then favors plaque rupture.7 25 Interestingly, it was recently demonstrated that both sCD40L and membrane-bound CD40L are potent inducers and activators of MMPs in macrophages and vascular SMCs but do not affect the expression of their inhibitors, tissue inhibitors of MMPs.14 15 Furthermore, enhanced CD40L-CD40 interaction may promote thrombotic activity by enhancing tissue-factor expression in macrophages and through the direct regulation of endothelium-procoagulant activity.15 16 26 Thus, although not specific for angina10 12 and without being the ultimate cause of this disease, CD40 activation may lead to procoagulant responses and MMP activation which, in patients with an preexisting atherosclerotic lesion, ultimately may lead to plaque rupture and the development of an acute coronary syndrome. However, other factors not necessarily related to enhanced CD40L-CD40 interaction also seem to be involved in this process (eg, enhanced apoptosis of vascular SMCs and levels of "rupture-inhibitory" mediators such as tissue inhibitors of MMPs),14 27 and the exact contributory role of CD40L will have to further elucidated.
We believe that the increased serum levels of sCD40L in patients with unstable angina are not only a marker of immune activation, but may also be involved in pathogenic processes in these patients. sCD40L in the circulation may pass through damaged atherosclerotic endothelium and come into direct contact with cells inside the lesion. However, even more importantly, sCD40L may activate circulating leukocytes to enhance the release of proinflammatory cytokines,28 increase the expression of adhesion molecules10 28 and, as demonstrated in the present study, enhance the release of CC-chemokines (ie, MCP-1) in mononuclear cells. Such an activation of the circulating leukocytes may be facilitated at the endothelium outside an atherosclerotic plaque, with upregulation of adhesion molecules and tethering of circulating cells. These inflammatory responses, possibly mediated by sCD40L, may further promote the infiltration of activated leukocytes into the atherosclerotic lesion, which in turn, may directly activate SMCs, macrophages, and T cells inside the vessel wall.14 15
In addition to increased levels of sCD40L, patients with unstable angina also had enhanced expression of membrane-bound CD40L on both CD4+ and CD8+ T cells in peripheral blood. Advanced human atheromata contain numerous T cells, and relevant to the process of plaque rupture, T cells seem to account for almost 20% of the cells in the shoulder region of a plaque.29 These T cells are predominantly of the CD4+ subset14 29 and, interestingly, we found increased percentages of CD4+ T cells expressing CD40L only in patients with unstable angina, further supporting a role for CD4+ T cells in the development of acute coronary syndromes. However, although CD40L+ T cells have been found within human atherosclerotic plaques and not in nonatherosclerotic human arteries,13 forthcoming studies will have to clarify whether this increase in the numbers of CD40L+ T cells also exists within atherosclerotic lesions in the coronary arteries of patients with unstable angina.
A major finding in the present study was that platelets could
release large amounts of sCD40L on activation, and the marked and rapid
release of sCD40L after SFLLRN stimulation and the complete inhibition
of sCD40L by preincubation with prostaglandin
E1 (N.O. Solum, PhD, and P. Aukrust, MD, PhD,
unpublished data, 1998) suggest that this protein is stored in
the -granules within the platelets like other proteins secreted
from these cells. Notably, it seems that platelets from patients
with unstable angina are characterized by markedly decreased
intracellular sCD40L levels as well as decreased release of sCD40L on
SFLLRN stimulation. These findings probably reflect the fact that PRP
in patients with unstable angina contains a higher percentage of
degranulated platelets, resulting in decreased levels of sCD40L in
platelet pellets and in stimulated supernatants, but with no change
in the percent release from the nondegranulated platelets (data not
shown). From time to time, circulating platelets in patients with
unstable angina may well encounter a secretion-inducing "event,"
eg, contact with "foreign surfaces" at an atherosclerotic lesion,
and such stimuli may possibly be potentiated by enhanced levels of
proinflammatory cytokines, eg, TNF.18 Such an
in vivo activation may induce a marked degranulation in a small but
significant proportion of platelets, resulting in a persistently
higher proportion of degranulated platelets in these patients. A
similar pattern of decreased SFLLRN-stimulated platelet activation
ex vivo, reflecting enhanced platelet activation in vivo, has
recently been reported in patients with septic shock30 and
AIDS.18 Whatever the mechanisms, these extensively
activated platelets in patients with unstable angina may,
by expressing and releasing CD40L, contribute to inflammatory
reactions, resulting in MMP activation and procoagulant activity. This
activation further destabilizes the atherosclerotic plaque which, in
turn, may further enhance platelet activation and thrombus
formation, causing a vicious circle to operate in acute
coronary syndromes.
We found no association between the use of aspirin and serum levels of
sCD40L. In fact, 90% of the patients with both stable and unstable
angina used this medication, but only the latter group had indications
of marked platelet activation in vivo. Thus, although aspirin is
extensively used in angina patients and may inhibit some platelet
functions, more potent platelet inhibitors may be
required to inhibit the enhanced release of sCD40L from these cells.
Interestingly, a recent study in patients with unstable angina
demonstrated beneficial effects of a platelet
glycoprotein IIb/IIIa inhibitor, which is a
potent inhibitor of platelet function, beyond that of
aspirin.31
Although thrombin and contact with an atherosclerotic lesion may trigger the release of sCD40L from platelets, the triggers of T-cell activation in patients with unstable angina will have to be further elucidated. Interestingly, we found that anti-CD3/anti-CD28 stimulation was a potent inducer of sCD40L release from T cells, and such stimulation also enhances the expression of membrane-bound CD40L in these cells.32 The in vivo correlate to such stimulation may be T-cell activation induced by persistent stimulation of antigen-presenting cells. Some have suggested that long-term infections, eg, Chlamydia pneumonia, are involved in the pathogenesis of angina,33 and persistent stimulation by microbial antigens might well lead to enhanced CD40L expression on T cells. However, the "CD40-CD40L hypothesis" clearly does not depend on the "infectious hypothesis," and several other factors may well lead to T-cell activation in these patients. For example, enhanced oxidative stress and oxidized-LDL might also lead to increased CD40L levels and T-cell activation through monocyte activation or direct effects on T cells.34 35
One may argue that elevated levels of CD40L are a consequence rather than a cause of unstable angina, and our data do not permit any definitive conclusion on this important issue. The marked rise in sCD40L levels after mechanically induced plaque rupture by PTCA may suggest that raised sCD40L levels are a secondary phenomenon. However, the fact that plaque rupture may induce further elevation of sCD40L does not exclude a pathogenic role for CD40L in this process. In fact, several "minor plaque ruptures" may possibly precede the onset of an acute coronary event and, although not the ultimate cause of unstable angina, enhanced CD40L levels may, at least in a subgroup of patients, contribute to the progression and aggravation of this disease, leading to enhanced destabilization of the coronary plaque. Thus, elevated CD40L levels may be both a cause and a consequence of plaque rupture, possibly representing a vicious circle operating in patients with acute coronary syndromes, and therapeutical modalities that downregulate CD40L-CD40 interaction may represent a new therapeutical approach in these patients.
|
Acknowledgments |
|---|
We thank Vigdis Bjerkeli, Karin Lund Pah, and Turid Pedersen for their excellent technical assistance. We also thank Dr. Elaine K. Thomas at Immunex Corp, Seattle, Wash for providing the trimeric human CD40L/leucine zipper fusion protein and the monoclonal mouse anti-human CD40L. This work was supported by the Norwegian Council of Cardiovascular Disease, the Research Council of Norway, Anders Jahre's Foundation, and the Medinnova Foundation.
|
Footnotes |
|---|
Correspondenc to Pål Aukrust, Medical Department, Rikshospitalet, N-0027 Oslo, Norway.
Received February 1, 1999; revision received May 20, 1999; accepted May 20, 1999.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
1. Ikeda H, Takajo Y, Ichiki K, Ueno T, Maki S, Noda T, Sugi K, Imaizumi T. Increased soluble form of P-selectin in patients with unstable angina. Circulation. 1995;92:1693–1696.
2.
Biasucci LM, Vitelli A, Liuzzo G, Altamura S,
Caligiuri G, Monaco C, Rbuzzi AG, Ciliberto G, Maseri A. Elevated
levels of interleukin-6 in unstable angina. Circulation. 1996;94:874–877.
3.
Serneri GGN, Prisco D, Martini F, Gori AM, Brunelli T,
Poggesi L, Rostagno C, Gensini GF, Abbata R. Acute T-cell activation is
detectable in unstable angina. Circulation. 1997;95:1806–1812.
4.
Mazzone A, De Servi S, Ricevuti G, Mazzucchelli I,
Fossati G, Pasotti F, Specchia G, Notario A. Increased expression of
neutrophil and monocyte adhesion molecules in unstable coronary
artery disease. Circulation. 1993;88:358–363.
5. Ross R. The pathogenesis of atherosclerosis in the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
6.
Entmann ML, Ballantyne CM. Inflammation and acute
coronary syndromes. Circulation. 1993;88:800–803.
7.
Davies MJ. Reactive oxygen species,
metalloproteinases, and plaque stability. Circulation. 1998;97:2382–2383.
8.
Saren P, Welgus HG, Kovanene PT. TNF- and
IL-1ß selectively induce expression of 92-kDa gelatinase by human
macrophages. J Immunol. 1996;157:4159–4165.[Abstract]
9. Hollenbaug D, Grosmaire RS, Kullas CD, Chalupny NJ, Braesch-Andersen S, Noelle RJ, Stamenkovic I, Ledbetter JA, Aruffo A. The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J. 1992;11:4313–4321.[Medline] [Order article via Infotrieve]
10. Grewal IS, Flavell RA. The CD40 ligand. Immunol Res. 1997;16:59–70.[Medline] [Order article via Infotrieve]
11. Henn V, Slupsky JS, Gräfe M, Anagnostopoulos I, Förster R, Müller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998;351:591–594.
12. Buhlmann JE, Noelle RJ. Therapeutic potential for blockade of the CD40 ligand, gp39. J Clin Immunol. 1996;16:83–89.[Medline] [Order article via Infotrieve]
13.
Mach F, Schönbeck U, Sukhova GK, Bourcier T,
Bonnefoy JY, Pober JS, Libby P. Functional CD40 ligand is expressed on
human vascular endothelial cells, smooth muscle cells,
and macrophages: implication for CD40-CD40 ligand signaling in
atherosclerosis. Proc Natl Acad Sci U S A. 1997;94:1931–1936.
14.
Schönbeck U, Mach F, Sukhova GK, Murphy C,
Bonnefoy J-Y, Fabunmi RP, Libby P. Regulation of matrix
metalloproteinase expression in human vascular smooth muscle cells by T
lymphocytes: a role for CD40 signaling in plaque rupture? Circ
Res. 1997;81:448–454.
15.
Mach F, Schönbeck U, Bonnefoy J-Y, Pober JS,
Libby P. Activation of monocyte/macrophage functions related to
acute atheroma complication by ligation of CD40: induction
of collagenase, stromelysin, and tissue factor.
Circulation. 1997;96:396–399.
16. Zhou L, Stordeur P, de Lavareille A, Thielemans K, Capel P, Goldman M, Pradier O. CD40 engagement on endothelial cells promotes tissue factor-dependent procoagulant activity. Thromb Haemost. 1998;79:1025–1028.[Medline] [Order article via Infotrieve]
17.
Braunwald E. Unstable angina: a classification.
Circulation. 1993;80:410–414.
18.
Holme PA, Müller F, Solum NO, Brosstad F,
Frøland SS, Aukrust P. Enhanced activation of platelets with
abnormal release of RANTES in HIV-1 infection. FASEB J. 1998;12:79–90.
19.
Aandahl EM, Aukrust P, Skålhegg BS, Müller F,
Frøland SS, Hansson V, Taskén K. Protein kinase type I
antagonist restores immune responses of T-cells from
HIV-infected patients. FASEB J. 1998;12:855–862.
20.
Aukrust P, Ueland T, Müller F, Andreassen AK,
Nordøy I, Aas H, Kjekshus J, Simonsen S, Frøland SS, Gullestad L.
Elevated circulating levels of C-C chemokines in patients with
congestive heart failure. Circulation. 1998;97:1136–1143.
21. Nelken L, Coughlin S, Gordon D, Wilkox J. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991;88:1121–1127.
22. Kiener PA, Moran-Davis P, Rankin BM, Wahl AF, Aruffo A, Hollenbaugh D. Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J Immunol. 1995;155:4917–4925.[Abstract]
23. Fransisco JA, Kiener PA, Moran-Davis P, Ledbetter JA, Siegall CB. Cytokine activation sensitizes human monocytic and endothelial cells to the cytotoxic effects of an anti-CD40 immunotoxin. J Immunol. 1996;157:1652–1658.[Abstract]
24. Grammer AC, Bergman MC, Miura Y, Fujita K, Davis LS, Lipsky PE. The CD40 ligand expressed by human B cells costimulates B cell responses. J Immunol.. 1995;154:4996–5010.[Abstract]
25. Galis ZS, Sukhova GK, Libby P. Microscopic localization of active proteases by in situ zymography: detection of matrix metalloproteinase activity in vascular tissue. FASEB J. 1995;9:974–980.[Abstract]
26. Miller DL, Yaron R, Yellin MJ. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression. J Leukoc Biol. 1998;63:373–379.[Abstract]
27.
Geng YJ, Henderson LE, Levesque EB, Muszynski M, Libby
P. Fas is expressed in human atherosclerotic intima and promotes
apoptosis of cytokine-primed human vascular smooth
muscle cells. Arterioscler Thromb Vasc Biol. 1997;17:2200–2208.
28. Noelle RJ. CD40 and its ligand in host defense. Immunity. 1996;4:415–419.[Medline] [Order article via Infotrieve]
29. Jonasson L, Holm J, Skalli O, Bondjerd G, Hansson GK. Regional accumulations of T cells, macrophages and smooth muscle cells in the human atherosclerotic plaque. Atherosclerosis. 1986;6:131–138.
30. Lundahl TH, Petersson J, Fagerberg IH, Berg S, Lindahl TH. Impaired platelet function correlates with multi-organ dysfunction. Platelets. 1998;9:223–225.
31.
The PARAGON Investigators. International, randomized,
controlled trial of Lamifiban (a platelet glycoprotein
IIb/IIIa inhibitor), heparin, or both in unstable angina.
Circulation. 1998;97:2386–2395.
32. Klaus SJ, Pinchuk LM, Ochs HD, Law C-L, Franslow WC, Armitage RJ, Clark EA. Costimulation through CD28 enhances T cell-dependent B cell activation via CD40-CD40L interaction. J Immunol. 1994;152:5643–5652.[Abstract]
33. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997;350:430–436.[Medline] [Order article via Infotrieve]
34.
Jovinge S, Ares MPS, Kallin B, Nilsson J. Human
monocytes/macrophages release TNF- in response to
Ox-LDL. Arterioscler Thromb Vasc Biol. 1996;16:1573–1579.
35. Schreck R, Rieber P, Baeuerle PA. Reactive oxygen species intermediates as apparently widely used messengers in the activation of the NF-kB transcription factor and HIV-1. EMBO J. 1991;10:2247–2258.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  C. Antoniades, C. Bakogiannis, D. Tousoulis, A. S. Antonopoulos, and C. Stefanadis The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J. Am. Coll. Cardiol., August 18, 2009; 54(8): 669 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ueland, K. Otterdal, T. Lekva, B. Halvorsen, A. Gabrielsen, W. J. Sandberg, G. Paulsson-Berne, T. M. Pedersen, L. Folkersen, L. Gullestad, et al. Dickkopf-1 Enhances Inflammatory Interaction Between Platelets and Endothelial Cells and Shows Increased Expression in Atherosclerosis Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1228 - 1234. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Li Platelet-lymphocyte cross-talk J. Leukoc. Biol., May 1, 2008; 83(5): 1069 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Duygu, V. Barisik, H. Kurt, U. Turk, E. Ercan, and S. Kose Prognostic value of plasma soluble CD40 ligand in patients with chronic non-valvular atrial fibrillation Europace, February 1, 2008; 10(2): 210 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.O. Kraaijeveld, S.C.A. de Jager, W.J. de Jager, B.J. Prakken, S.R. McColl, I. Haspels, H. Putter, T.J.C. van Berkel, L. Nagelkerken, J.W. Jukema, et al. CC Chemokine Ligand-5 (CCL5/RANTES) and CC Chemokine Ligand-18 (CCL18/PARC) Are Specific Markers of Refractory Unstable Angina Pectoris and Are Transiently Raised During Severe Ischemic Symptoms Circulation, October 23, 2007; 116(17): 1931 - 1941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Inami, S. Nomura, Y. Kimura, K. Yamada, H. Nakamori, N. Takahashi, S. Fukuhara, and T. Iwasaka Evaluation of Platelet and Leukocyte Functions in Effort Angina Patients Using High Shear Conditions in Small-Sized Collagen Bead Columns Clinical and Applied Thrombosis/Hemostasis, October 1, 2007; 13(4): 428 - 431. [Abstract] [PDF]
|
|
|
|
|
|
J. Chen, L. Chen, G. Wang, and H. Tang Cholesterol-Dependent and -Independent CD40 Internalization and Signaling Activation in Cardiovascular Endothelial Cells Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 2005 - 2013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Ivandic, E. Spanuth, D. Haase, H.-G. Lestin, and H. A. Katus Increased Plasma Concentrations of Soluble CD40 Ligand in Acute Coronary Syndrome Depend on in Vitro Platelet Activation Clin. Chem., July 1, 2007; 53(7): 1231 - 1234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Prontera, N. Martelli, V. Evangelista, E. D'Urbano, S. Manarini, A. Recchiuti, A. Dragani, C. Passeri, G. Davi, and M. Romano Homocysteine Modulates the CD40/CD40L System J. Am. Coll. Cardiol., June 5, 2007; 49(22): 2182 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Steinhubl, J. J. Badimon, D. L. Bhatt, J.-M. Herbert, and T. F. Luscher Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease Vascular Medicine, May 1, 2007; 12(2): 113 - 122. [Abstract] [PDF]
|
|
|
|
|
|
J. Ruef, M. Browatzki, C. A. Pfeiffer, J. Schmidt, and R. Kranzhofer Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2 Vascular Medicine, February 1, 2007; 12(1): 23 - 27. [Abstract] [PDF]
|
|
|
|
|
|
H. Kosuge, J.-i. Suzuki, G. Haraguchi, N. Koga, Y. Maejima, M. Inobe, M. Isobe, and T. Uede Critical Role of Inducible Costimulator Signaling in the Development of Arteriosclerosis Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2660 - 2665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Otterdal, C. Smith, E. Oie, T. M. Pedersen, A. Yndestad, E. Stang, K. Endresen, N. O. Solum, P. Aukrust, and J. K. Damas Platelet-derived LIGHT induces inflammatory responses in endothelial cells and monocytes Blood, August 1, 2006; 108(3): 928 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Malarstig, B. Lindahl, L. Wallentin, and A. Siegbahn Soluble CD40L Levels Are Regulated by the -3459 A>G Polymorphism and Predict Myocardial Infarction and the Efficacy of Antithrombotic Treatment in Non-ST Elevation Acute Coronary Syndrome Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1667 - 1673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Heitzer, V. Rudolph, E. Schwedhelm, M. Karstens, K. Sydow, M. Ortak, P. Tschentscher, T. Meinertz, R. Boger, and S. Baldus Clopidogrel Improves Systemic Endothelial Nitric Oxide Bioavailability in Patients With Coronary Artery Disease: Evidence for Antioxidant and Antiinflammatory Effects Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1648 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Antoniades, D. Tousoulis, C. Vasiliadou, E. Stefanadi, K. Marinou, and C. Stefanadis Genetic Polymorphisms of Platelet Glycoprotein Ia and the Risk for Premature Myocardial Infarction: Effects on the Release of sCD40L During the Acute Phase of Premature Myocardial Infarction J. Am. Coll. Cardiol., May 16, 2006; 47(10): 1959 - 1966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Weber, B. Rabenau, M. Stanisch, A. Elsaesser, V. Mitrovic, C. Heeschen, and C. Hamm Influence of Sample Type and Storage Conditions on Soluble CD40 Ligand Assessment Clin. Chem., May 1, 2006; 52(5): 888 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Sandberg, A. Yndestad, E. Oie, C. Smith, T. Ueland, O. Ovchinnikova, A.-K. L. Robertson, F. Muller, A. G. Semb, H. Scholz, et al. Enhanced T-Cell Expression of RANK Ligand in Acute Coronary Syndrome: Possible Role in Plaque Destabilization Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 857 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Holm, T. Ueland, B. Halvorsen, A. Hognestad, A. G.V. Holm, R. Wergeland, L. Gullestad, P. Aukrust, and J. Kjekshus A Protective Anti-Inflammatory Phenotype in High-Risk Individuals Who Do Not Develop Coronary Artery Disease J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1085 - 1086. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kobayashi, Y. Nishimura, T. Shimada, S. Yoshimura, Y. Funada, M. Satouchi, and M. Yokoyama Effect of Continuous Positive Airway Pressure on Soluble CD40 Ligand in Patients With Obstructive Sleep Apnea Syndrome Chest, March 1, 2006; 129(3): 632 - 637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A K Mitra and D K Agrawal In stent restenosis: bane of the stent era. J. Clin. Pathol., March 1, 2006; 59(3): 232 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Vorchheimer and R. Becker Platelets in Atherothrombosis Mayo Clin. Proc., January 1, 2006; 81(1): 59 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Koh, S. H. Han, and M. J. Quon Inflammatory Markers and the Metabolic Syndrome: Insights From Therapeutic Interventions J. Am. Coll. Cardiol., December 6, 2005; 46(11): 1978 - 1985. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chakrabarti, S. Varghese, O. Vitseva, K. Tanriverdi, and J. E. Freedman CD40 Ligand Influences Platelet Release of Reactive Oxygen Intermediates Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2428 - 2434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Davis and M.-H. Zou CD40 Ligand-Dependent Tyrosine Nitration of Prostacyclin Synthase In Vivo Circulation, October 4, 2005; 112(14): 2184 - 2192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Scholz, W. Sandberg, J. K. Damas, C. Smith, A. K. Andreassen, L. Gullestad, S. S. Froland, A. Yndestad, P. Aukrust, and B. Halvorsen Enhanced Plasma Levels of LIGHT in Unstable Angina: Possible Pathogenic Role in Foam Cell Formation and Thrombosis Circulation, October 4, 2005; 112(14): 2121 - 2129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. de Lemos, A. Zirlik, U. Schonbeck, N. Varo, S. A. Murphy, A. Khera, D. K. McGuire, G. Stanek, H. S. Lo, R. Nuzzo, et al. Associations Between Soluble CD40 Ligand, Atherosclerosis Risk Factors, and Subclinical Atherosclerosis: Results from the Dallas Heart Study Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2192 - 2196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Keaney Jr Circulating Biomarkers in Acute Coronary Syndromes: Something Different or More of the Same? Circulation, August 9, 2005; 112(6): 778 - 780. [Full Text] [PDF]
|
|
|
|
|
|
K. Hayashida, N. Kume, T. Murase, M. Minami, D. Nakagawa, T. Inada, M. Tanaka, A. Ueda, G. Kominami, H. Kambara, et al. Serum Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels Are Elevated in Acute Coronary Syndrome: A Novel Marker for Early Diagnosis Circulation, August 9, 2005; 112(6): 812 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Elzey, J. F. Grant, H. W. Sinn, B. Nieswandt, T. J. Waldschmidt, and T. L. Ratliff Cooperation between platelet-derived CD154 and CD4+ T cells for enhanced germinal center formation J. Leukoc. Biol., July 1, 2005; 78(1): 80 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pfutzner, N. Marx, G. Lubben, M. Langenfeld, D. Walcher, T. Konrad, and T. Forst Improvement of Cardiovascular Risk Markers by Pioglitazone Is Independent From Glycemic Control: Results From the Pioneer Study J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1925 - 1931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. A. Ajijola, P. J. Goldschmidt-Clermont, and L. L. Satterwhite CD40 Ligand: Not Bad to the Bone (Marrow), After All Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1088 - 1090. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ueland, P. Aukrust, A. Yndestad, K. Otterdal, S. S. Froland, K. Dickstein, J. Kjekshus, L. Gullestad, and J. K. Damas Soluble CD40 ligand in acute and chronic heart failure Eur. Heart J., June 1, 2005; 26(11): 1101 - 1107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Halldorsdottir, J. Stoker, R. Porche-Sorbet, and C. S. Eby Soluble CD40 Ligand Measurement Inaccuracies Attributable to Specimen Type, Processing Time, and ELISA Method Clin. Chem., June 1, 2005; 51(6): 1054 - 1057. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Varo, P. Libby, R. Nuzzo, J. Italiano, A. Doria, and U. Schonbeck Elevated release of sCD40L from platelets of diabetic patients by thrombin, glucose and advanced glycation end products Diabetes and Vascular Disease Research, May 1, 2005; 2(2): 81 - 87. [Abstract] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 G. K. Hansson Inflammation, Atherosclerosis, and Coronary Artery Disease N. Engl. J. Med., April 21, 2005; 352(16): 1685 - 1695. [Full Text] [PDF]
|
|
|
|
|
|
V. Sanguigni, D. Ferro, P. Pignatelli, M. Del Ben, T. Nadia, M. Saliola, R. Sorge, and F. Violi CD40 ligand enhances monocyte tissue factor expression and thrombin generation via oxidative stress in patients with hypercholesterolemia J. Am. Coll. Cardiol., January 4, 2005; 45(1): 35 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Solanilla, J.-M. Pasquet, J.-F. Viallard, C. Contin, C. Grosset, J. Dechanet-Merville, M. Dupouy, M. Landry, F. Belloc, P. Nurden, et al. Platelet-associated CD154 in immune thrombocytopenic purpura Blood, January 1, 2005; 105(1): 215 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ueland, R. Jemtland, K. Godang, J. Kjekshus, A. Hognestad, T. Omland, I. B. Squire, L. Gullestad, J. Bollerslev, K. Dickstein, et al. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction J. Am. Coll. Cardiol., November 16, 2004; 44(10): 1970 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Frossard, I. Fuchs, J. M. Leitner, K. Hsieh, M. Vlcek, H. Losert, H. Domanovits, W. Schreiber, A. N. Laggner, and B. Jilma Platelet Function Predicts Myocardial Damage in Patients With Acute Myocardial Infarction Circulation, September 14, 2004; 110(11): 1392 - 1397. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Vishnevetsky, V. A Kiyanista, and P. J Gandhi CD40 Ligand: A Novel Target in the Fight Against Cardiovascular Disease Ann. Pharmacother., September 1, 2004; 38(9): 1500 - 1508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Akbiyik, D. M. Ray, K. F. Gettings, N. Blumberg, C. W. Francis, and R. P. Phipps Human bone marrow megakaryocytes and platelets express PPAR{gamma}, and PPAR{gamma} agonists blunt platelet release of CD40 ligand and thromboxanes Blood, September 1, 2004; 104(5): 1361 - 1368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Damas, K. Otterdal, A. Yndestad, H. Aass, N. O. Solum, S. S. Froland, S. Simonsen, P. Aukrust, and A. K. Andreassen Soluble CD40 Ligand in Pulmonary Arterial Hypertension: Possible Pathogenic Role of the Interaction Between Platelets and Endothelial Cells Circulation, August 24, 2004; 110(8): 999 - 1005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Lindstedt, M. J. Leskinen, and P. T. Kovanen Proteolysis of the Pericellular Matrix: A Novel Element Determining Cell Survival and Death in the Pathogenesis of Plaque Erosion and Rupture Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1350 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kinlay, G. G. Schwartz, A. G. Olsson, N. Rifai, W. J. Sasiela, M. Szarek, P. Ganz, P. Libby, and for the Myocardial Ischemia Reduction with Aggress Effect of Atorvastatin on Risk of Recurrent Cardiovascular Events After an Acute Coronary Syndrome Associated With High Soluble CD40 Ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Circulation, July 27, 2004; 110(4): 386 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Smith, A. Yndestad, B. Halvorsen, T. Ueland, T. Waehre, K. Otterdal, H. Scholz, K. Endresen, L. Gullestad, S. S. Froland, et al. Potential anti-inflammatory role of activin A in acute coronary syndromes J. Am. Coll. Cardiol., July 21, 2004; 44(2): 369 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. I. Furman, L. A. Krueger, M. D. Linden, M. R. Barnard, A. L. Frelinger III, and A. D. Michelson Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2319 - 2325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Aukrust, J. K. Damas, and N. O. Solum Soluble CD40 ligand and platelets: self-perpetuating pathogenic loop in thrombosis and inflammation? J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2326 - 2328. [Full Text] [PDF]
|
|
|
|
|
|
Z. Xiao and P. Theroux Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome J. Am. Coll. Cardiol., June 2, 2004; 43(11): 1982 - 1988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Granger, T. Vowinkel, and T. Petnehazy Modulation of the Inflammatory Response in Cardiovascular Disease Hypertension, May 1, 2004; 43(5): 924 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kaufman, P. J. Sime, and R. P. Phipps Expression of CD154 (CD40 Ligand) by Human Lung Fibroblasts: Differential Regulation by IFN-{gamma} and IL-13, and Implications for Fibrosis J. Immunol., February 1, 2004; 172(3): 1862 - 1871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Roselli, T. C. Mineo, S. Basili, F. Martini, S. Mariotti, S. Aloe, G. Del Monte, V. Ambrogi, A. Spila, R. Palmirotta, et al. Soluble CD40 Ligand Plasma Levels in Lung Cancer Clin. Cancer Res., January 15, 2004; 10(2): 610 - 614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, C. Ferri, G. Desideri, L. Paloscia, G. Materazzo, M. Mascellanti, M. Fazia, A. Iezzi, C. Cuccurullo, B. Pini, et al. Preprocedural Level of Soluble CD40L Is Predictive of Enhanced Inflammatory Response and Restenosis After Coronary Angioplasty Circulation, December 2, 2003; 108(22): 2776 - 2782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Szmitko, C.-H. Wang, R. D. Weisel, J. R. de Almeida, T. J. Anderson, and S. Verma New Markers of Inflammation and Endothelial Cell Activation: Part I Circulation, October 21, 2003; 108(16): 1917 - 1923. [Full Text] [PDF]
|
|
|
|
 |
|
 O. J de Boer, A. E Becker, and A. C van der Wal T lymphocytes in atherogenesis--functional aspects and antigenic repertoire Cardiovasc Res, October 15, 2003; 60(1): 78 - 86. [Full Text] [PDF]
|
|
|
|
 |
|
 K. S. S. Prasad, P. Andre, M. He, M. Bao, J. Manganello, and D. R. Phillips Soluble CD40 ligand induces {beta}3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling PNAS, October 14, 2003; 100(21): 12367 - 12371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Danese, J A Katz, S Saibeni, A Papa, A Gasbarrini, M Vecchi, and C Fiocchi Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients Gut, October 1, 2003; 52(10): 1435 - 1441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Varo, J. A. de Lemos, P. Libby, D. A. Morrow, S. A. Murphy, R. Nuzzo, C. M. Gibson, C. P. Cannon, E. Braunwald, and U. Schonbeck Soluble CD40L: Risk Prediction After Acute Coronary Syndromes Circulation, September 2, 2003; 108(9): 1049 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Tousoulis, G Davies, C Stefanadis, P Toutouzas, and J A Ambrose Inflammatory and thrombotic mechanisms in coronary atherosclerosis Heart, September 1, 2003; 89(9): 993 - 997. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Heitzer, I. Ollmann, K. Koke, T. Meinertz, and T. Munzel Platelet Glycoprotein IIb/IIIa Receptor Blockade Improves Vascular Nitric Oxide Bioavailability in Patients With Coronary Artery Disease Circulation, August 5, 2003; 108(5): 536 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Bereczki, E. Nagy, A. Pal, M. T. Magyar, J. Balla, G. J. Blake, R. J. Ostfeld, E. K. Yucel, N. Varo, U. Schonbeck, et al. Should Soluble CD40 Ligand Be Measured From Serum or Plasma Samples? * Arterioscler Thromb Vasc Biol, June 12, 2003; 23(6): 1129 - 1130. [Full Text] [PDF]
|
|
|
|
|
|
J. K. Damas, T. Waehre, A. Yndestad, K. Otterdal, A. Hognestad, N. O. Solum, L. Gullestad, S. S. Froland, and P. Aukrust Interleukin-7-Mediated Inflammation in Unstable Angina: Possible Role of Chemokines and Platelets Circulation, June 3, 2003; 107(21): 2670 - 2676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Varo, D. Vicent, P. Libby, R. Nuzzo, A. L. Calle-Pascual, M. R. Bernal, A. Fernandez-Cruz, A. Veves, P. Jarolim, J. J. Varo, et al. Elevated Plasma Levels of the Atherogenic Mediator Soluble CD40 Ligand in Diabetic Patients: A Novel Target of Thiazolidinediones Circulation, June 3, 2003; 107(21): 2664 - 2669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. P. Inwald, A. McDowall, M. J. Peters, R. E. Callard, and N. J. Klein CD40 Is Constitutively Expressed on Platelets and Provides a Novel Mechanism for Platelet Activation Circ. Res., May 16, 2003; 92(9): 1041 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Marx, A. Imhof, J. Froehlich, L. Siam, J. Ittner, G. Wierse, A. Schmidt, W. Maerz, V. Hombach, and W. Koenig Effect of Rosiglitazone Treatment on Soluble CD40L in Patients With Type 2 Diabetes and Coronary Artery Disease Circulation, April 22, 2003; 107(15): 1954 - 1957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Heeschen, S. Dimmeler, C. W. Hamm, M. J. van den Brand, E. Boersma, A. M. Zeiher, M. L. Simoons, and the CAPTURE Study Investigators Soluble CD40 Ligand in Acute Coronary Syndromes N. Engl. J. Med., March 20, 2003; 348(12): 1104 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Nannizzi-Alaimo, V. L. Alves, and D. R. Phillips Inhibitory Effects of Glycoprotein IIb/IIIa Antagonists and Aspirin on the Release of Soluble CD40 Ligand During Platelet Stimulation Circulation, March 4, 2003; 107(8): 1123 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-L. Wang, Y.-T. Wu, C.-A. Liu, M.-W. Lin, C.-J. Lee, L.-T. Huang, and K. D. Yang Expression of CD40 Ligand on CD4+ T-Cells and Platelets Correlated to the Coronary Artery Lesion and Disease Progress in Kawasaki Disease Pediatrics, February 1, 2003; 111(2): e140 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Semb, S. van Wissen, T. Ueland, T. Smilde, T. Waehre, M. D. Tripp, S. S. Froland, J. J. P. Kastelein, L. Gullestad, T. R. Pedersen, et al. Raised serum levels of soluble CD40 ligand in patients with familial hypercholesterolemia: downregulatory effect of statin therapy J. Am. Coll. Cardiol., January 15, 2003; 41(2): 275 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Schonbeck, N. Gerdes, N. Varo, R. S. Reynolds, D. B. Horton, U. Bavendiek, L. Robbie, P. Ganz, S. Kinlay, and P. Libby Oxidized Low-Density Lipoprotein Augments and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Limit CD40 and CD40L Expression in Human Vascular Cells Circulation, December 3, 2002; 106(23): 2888 - 2893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Andre, L. Nannizzi-Alaimo, S. K. Prasad, and D. R. Phillips Platelet-Derived CD40L: The Switch-Hitting Player of Cardiovascular Disease Circulation, August 20, 2002; 106(8): 896 - 899. [Full Text] [PDF]
|
|
|
|
|
|
C. Urbich, E. Dernbach, A. Aicher, A. M. Zeiher, and S. Dimmeler CD40 Ligand Inhibits Endothelial Cell Migration by Increasing Production of Endothelial Reactive Oxygen Species Circulation, August 20, 2002; 106(8): 981 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, A. Mezzetti, E. Porreca, C. Di Febbo, M. Nutini, M. Fazia, A. Falco, F. Cuccurullo, and G. Davi Association Between Enhanced Soluble CD40L and Prothrombotic State in Hypercholesterolemia: Effects of Statin Therapy Circulation, July 23, 2002; 106(4): 399 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Nannizzi-Alaimo, M. H. Rubenstein, V. L. Alves, G. Y. Leong, D. R. Phillips, and H. K. Gold Cardiopulmonary Bypass Induces Release of Soluble CD40 Ligand Circulation, June 18, 2002; 105(24): 2849 - 2854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Viallard, A. Solanilla, B. Gauthier, C. Contin, J. Dechanet, C. Grosset, J.-F. Moreau, V. Praloran, P. Nurden, J.-L. Pellegrin, et al. Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis Blood, April 1, 2002; 99(7): 2612 - 2614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maseri and D. Cianflone Inflammation in acute coronary syndromes Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B8 - B13. [Abstract] [PDF]
|
|
|
|
|
|
U. Schonbeck and P. Libby CD40 Signaling and Plaque Instability Circ. Res., December 7, 2001; 89(12): 1092 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. AUKRUST, T. WAeHRE, J. K. DAMAS, L. GULLESTAD, and N. O. SOLUM Inflammatory role of platelets in acute coronary syndromes Heart, December 1, 2001; 86(6): 605 - 606. [Full Text] [PDF]
|
|
|
|
|
|
C D Garlichs, S Eskafi, D Raaz, A Schmidt, J Ludwig, M Herrmann, L Klinghammer, W G Daniel, and A Schmeisser Patients with acute coronary syndromes express enhanced CD40 ligand/CD154 on platelets Heart, December 1, 2001; 86(6): 649 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Garlichs, S. John, A. Schmei{beta}er, S. Eskafi, C. Stumpf, M. Karl, M. Goppelt-Struebe, R. Schmieder, and W. G. Daniel Upregulation of CD40 and CD40 Ligand (CD154) in Patients With Moderate Hypercholesterolemia Circulation, November 13, 2001; 104(20): 2395 - 2400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Schonbeck, N. Varo, P. Libby, J. Buring, and P. M. Ridker Soluble CD40L and Cardiovascular Risk in Women Circulation, November 6, 2001; 104(19): 2266 - 2268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.a. Aukrust, R. K. Berge, T. Ueland, E. Aaser, J. K. Damas, L. Wikeby, A. Brunsvig, F. Muller, K. Forfang, S. S. Froland, et al. Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes J. Am. Coll. Cardiol., February 1, 2001; 37(2): 485 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Phipps Atherosclerosis: The emerging role of inflammation and the CD40-CD40 ligand system PNAS, June 20, 2000; 97(13): 6930 - 6932. [Full Text] [PDF]
|
|
|
|
|
|
E. Lutgens, K. B. J. M. Cleutjens, S. Heeneman, V. E. Koteliansky, L. C. Burkly, and M. J. A. P. Daemen Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype PNAS, June 20, 2000; 97(13): 7464 - 7469. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Waldmann, R. Levy, and B. S. Coller Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy Hematology, January 1, 2000; 2000(1): 394 - 408. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||