Atherosclerotic Plaque Stability—What
Determines the Fate of a Plaque?
Bente Halvorsen, Kari Otterdal, Tuva B. Dahl, Mona Skjelland, Lars Gullestad,
Erik Øie and Pål Aukrust
Although the understanding of the underlying
pathology of atherosclerosis has improved in recent
years, the disease is still the main cause of death
globally. Current evidence has implicated the role of
inflammation in atherogenesis and plaque destabi-
lization. Thus, inflammatory cytokines may attenu-
ate interstitial collagen synthesis, increase matrix
degradation, and promote apoptosis in several
atheroma-associated cell types, and all these
cellular events may enhance plaque vulnerability.
Several cell types found within the lesion (ie,
monocyte/macrophages, T cells, mast cells, plate-
lets) contribute to this immune-mediated plaque
destabilization, and a better understanding of these
processes is a prerequisite for the development of
new treatment strategies in these individuals. Such
knowledge could also facilitate a better identifica-
tion of high-risk individuals. In the present study,
these issues will be discussed in more detail,
particularly focusing on the interactions between
matrix degradation, apoptotic, and inflammatory
processes in plaque destabilization.
© 2008 Elsevier Inc. All rights reserved.
A therosclerosis has affected humans since
antiquity (3000 BC to 400 AD). Extensive
macroscopic and microscopic evidences of ather-
osclerosis in the aorta and carotid have been
found in mummies (reviewed by Cullen et al1).
At present, atherosclerosis is the major cause of
coronary artery disease (CAD) causing 19
million deaths annually.2 Current knowledge
has revealed that diet, lifestyle (eg, smoking and
physical inactivity), and genetics are risk factors
for CAD, and a decade ago, lipid-lowering
therapy was expected to eliminate CAD and
other forms of atherosclerosis by the end of the
20th century. However, that optimistic predic-
tion needs revision and cardiovascular diseases
Progress in Cardiovascular Diseases, Vol. 51, No. 3 (November/December), 2008: pp 183-194
are expected to be the main cause of death
globally within the next 15 years, at least partly
due to the rapidly increasing prevalence in
developing countries and Eastern Europe and
the rising incidence of obesity and diabetes in
the Western world.3 Moreover, despite state-of-
the-art cardiovascular treatment, cardiovascular
diseases cause 38% of all deaths in North
America and are the most common cause of
death in European men younger than 65 years
and the second most common cause in women
(reviewed by Hansson4), suggesting that impor-
tant pathogenic mechanisms remain unmodified
by the present treatment modalities. Persistent
inflammation may represent such unmodified
mechanisms, and research trying to identify the
triggers for inflammation and to unravel the
details of inflammatory pathways in athero-
sclerosis may eventually furnish new therapeutic
targets in this disorder. However, before such a
goal can be achieved, it is of outmost importance
to develop a better understanding of the
pathogenic mechanisms in atherosclerosis and
plaque destabilization.
From the Research Institute for Internal Medicine,
Rik shospit alet Medi cal Center, Oslo, Norway,
Department of Neurology, Rikshospitalet Medical Center,
Oslo, Norway, Department of Cardiology, Rikshospitalet
Medical Center, Oslo, Norway, and Section of Clinical
Immunology and Infectious Diseases, Rikshospitalet
Medical Center, Oslo, Norway.
Address reprint requests to Bente Halvorsen, MSc, PhD,
Research Institute for Internal Medicine, Rikshospitalet
Medical Center, University of Oslo, Sognsvannsveien 20,
0027 Oslo, Norway. E-mail: bente.halvorsen@rr-research.no
0033-0620/$ - see front matter
© 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcad.2008.09.001
183
184 HALVORSEN ET AL

The Role of Inflammation in Acute Coronary Syndromes—Shifting

Atherogenesis and Plaque Focus from Stenotic Vessels to
Destabilization Plaque Disruption
Our classical view held that acute myocardial
Atherosclerosis is a chronic disease characterized
infarction (MI) usually occurred because of a
by 2 fundamental hallmarks: lipid accumulation
critically narrowed coronary arterial lumen, detect-
and inflammation. The interaction between these
able by angiography. However, careful pathologic
2 processes defines the principal pathogenesis
and angiographic studies in the 1980s determined
and distinguishes atherosclerosis from other
that fissuring or rupture of the thin fibrous cap of a
chronic inflammatory disorders. Atherosclerosis
coronary atheroma with preserved lumen often
is a progressive disease in which lipids, extra-
triggers acute fatal thrombosis. Thus, angiographic
cellular matrix (ECM), and activated vascular
studies have shown that the culprit lesion in acute
smooth muscle cells (VSMCs) accumulate in the
MI may not necessarily cause hemodynamically
arterial wall resulting in growth of an athero-
relevant (flow-limiting) stenosis of the coronary
sclerotic plaque. After the formation of the fatty
arteries. Moreover, several large clinical studies
streaks, the nascent atheroma typically evolves
have shown that, although cholesterol lowering
into a more fibrotic and complex lesion, which
with statins substantially reduces the occurrence of
eventually leads to clinical manifestation of CAD
acute adverse coronary events, such therapy
and other forms of atherosclerotic disorders.5
surprisingly produces only slight reduction in
Although the earliest process of atherosclero-
arterial obstruction estimated by angiography.7 A
sis is thought to be the accumulation of lipids in
striking difference between patients with unstable
the intima of arteries that supposedly results
and stable angina is the higher incidents of new
from endothelial dysfunction because of insult-
coronary events in the unstable group, and, notably,
induced damage, several lines of evidence have
in almost half of the cases such recurrent events are
shown that inflammation also plays a key role in
unrelated to the initial culprit lesion but arise from
atherogenesis.6 Hence, immune cells dominate
complications in other segments of the coronary
early atherosclerotic lesions, their effector mole-
vasculature. In fact, several angiographic and
cules accelerate progression of the lesions, and
angioscopic studies have revealed that all major
activation of inflammation can elicit acute
coronary arteries are widely diseased displaying
coronary syndromes (ACS) and transitory
multiple vulnerable plaques in unstable patients.
ischemic attack/stroke. In addition, classic risk
These new findings have shifted the goal of therapy
factors for cardiovascular disease such as hyper-
toward plaque stabilization rather than toward
lipidemia, hypertension, and diabetes seem to
enlargement of the lumen. To achieve such a goal,
promote their atherogenic effects at least partly
a better understanding of the biology of the
through inflammatory responses.4 Although the
atherosclerotic plaques and the processes leading
concept that atherosclerosis is an inflammatory
to plaque destabilization is needed.
disease is no longer controversial, the regulation
of these inflammatory processes as well as their
pathogenic consequences is not fully under-
Shifting from High-Risk Plaques to
stood. Moreover, although the participation of
inflammatory mediators in the atherosclerotic
High-Risk Patients
process has become widely recognized, the The characteristics of atherosclerotic plaques have
identification and characterization of the differ- been extensively studied during the last years, and
ent actors, as well as their relative importance, as listed in Table 1, there are several features
are not fulfilled. Also, although inflammatory characterizing a vulnerable lesion. However, a
processes such as infiltration and activation of recent consensus document proposed the term
leukocyte subsets into the atherosclerotic plaque vulnerable patient rather than vulnerable plaque to
have been shown to be involved in the triggering define patients at risk for ACS, MI, and sudden
of ACS, our knowledge of the immunopatho- cardiac death.11,12 These authors suggest that not
genic mechanisms in plaque destabilization is only vulnerable plaques but also other factors such
still limited. as blood (prone to thrombosis) and myocardial
ATHEROSCLEROTIC PLAQUE STABILITY
Table 1. Characteristics of Vulnerable
Atherosclerotic Plaque
Features Vulnerable plaque Stable plaque
Fibrous cap − +
Lipid-rich core + −
Inflammation + −
Neovascularization + −
Hemorrhage + −
Calcification − +
Matrix remodeling + −
Necrosis + −
Apoptosis ± ±
Table modified from Refs. [8-10].
(prone to fatal arrhythmia) variables should be
considered for cumulative risk assessment. Persis-
tent systemic and local inflammation seems also to
be an important feature of an unstable patient, and
the pan-coronary vulnerability during ACS could
potentially result from a widespread coronary
inflammation. Buffon et al6 have recently reported
a transcoronary neutrophil activation in patients
with unstable angina, occurring to a similar degree
in the presence or absence of the culprit lesion. In
addition, multiple studies have established inflam-
matory markers and in particular C-reactive
protein as risk predictors of future cardiovascular
events.13,14 Indeed, C-reactive protein has proven
remarkably robust as a marker of cardiovascular
risk and has been found to give a predictive value
beyond that of traditional risk factors in patients
with CAD, suggesting that low-grade systemic
inflammation may be an important feature of an
unstable patient.
Distinguishing between vulnerable and stable
patients, and a better understanding of the
pathogenic mechanisms of plaque destabilization
and triggering of ACS are major areas of current
cardiovascular research. This review will focus on
2 crucial mechanisms that take place in vulnerable
atherosclerotic plaques, namely, matrix degrada-
tion and apoptosis. We will also discuss how
various cell types as well as systemic and local
inflammation influence these processes (Fig 1).
Fibrous Cap Thinning—Imbalance
Between Matrix Synthesis
and Degradation
The formation of fibrous cap is an important step
in atherogenesis. This formation develops as a
result of a multifactorial process in which VSMCs
185
play a crucial role. Thus, the mutual activation of
T cells and macrophages results in production of
various cytokines and growth factors that stimu-
late VSMC proliferation, migration, as well as
their production of ECM. The influx and/or
proliferation of VSMCs will be one of the
determinants of whether an elastic fibrous cap
or thinning of the cap is formed. Increased influx
and proliferation of VSMCs will certainly stabi-
lize the plaque, but concomitantly cause a
narrowing of the arterial lumen potentially
leading to chronic ischemia. However, most
fatal acute MIs result from a fracture of the
plaque's fibrous cap,15 and migration of VSMCs
into the lesion could counteract this process,
underscoring that different pathogenic mechan-
isms may be operating in the chronic and
narrowing atherosclerotic process as compared
with the pathogenic mechanisms that promote
plaque destabilization. It seems that the strength
of the fibrous atherosclerotic cap depends on a
dynamic balance of collagen synthesis and
degradation, and, notably, several lines of evi-
dence suggest that inflammatory cytokines can
regulate both the expression of genes that direct
interstitial collagen synthesis and matrix metal-
loproteinases (MMPs) required to initiate the
breakdown of collagen fibrils.16 First, inflamma-
tory cytokines, such as interferon (IFN)-γ, a
product of activated T cells, can inhibit de novo
synthesis of interstitial collagen and induce
apoptosis in VSMCs,17 the major source of
collagen in the artery wall. Interestingly, mice
prone to atherosclerosis bearing a mutation of
the IFN-γ receptor show accumulation of col-
lagen in their lesions, suggesting increased
plaque stability.18 Second, inflammatory media-
tors markedly enhance the expression and
activity of MMPs. Thus, the resident macro-
phages have been identified as a major source of
several MMPs in human19 and experimental
atherosclerotic lesions,20 and the mechanism
responsible for expression and activation of
macrophage-derived MMPs seems to involve
both inflammatory cytokines and oxidative
stress. Interestingly, analysis of human atherect-
omy specimens revealed uniformly higher synth-
esis of MMPs by macrophages21 and VSMCs19 in
lesions from unstable vs stable angina, suggest-
ing the role of MMPs in ACS. Finally, although
inflammatory mediators induce MMP expres-
186 HALVORSEN ET AL

Fig 1. Characteristic features of vulnerable (left) and stable (right) atherosclerotic plaques. In the unstable plaque
(left), recruitment of inflammatory cells into the vessel wall causes a cascade of reactions such as tissue factor (TF)
secretion, MMP production, and generation of reactive oxygen species (ROS), which lead to matrix degradation
and weakening of the fibrous cap and subsequently thrombus formation. The stable plaque (right) is characterized
by a low-grade inflammation and enrichment of smooth muscle cells (SMCs) which stabilize the lesion. Notably,
certain MMP production is necessary for SMC capability to migrate and subsequently stabilize the atheroma.
*Apoptosis of endothelial cells and SMCs is a predominant feature in unstable plaque, whereas apoptosis of
macrophages is found to have an opposing role in the atherogenesis. Importantly, in early lesion macrophages
apoptosis will be rapidly cleared by efferocytosis (phagocytosis of apoptotic neighbor cells) and cause decreased
lesion progression. In contrast, in advanced plaque apoptotic macrophages will cause inefficient clearance and
promote postapoptotic necrosis and subsequently plaque rupture. **Smooth muscle cell–enriched cap will stabilize
the plaque.

sion, these matrix-degrading enzymes may again Matrix Metalloproteinases: A Complex

enhance the bioactivity of some inflammatory
cytokines (eg, tumor necrosis factor [TNF]-α
and IL-1β) by proteolytic cleavage. This
mutually activating interaction between MMPs
and inflammatory mediators may serve as a
positive-feedback loop promoting plaque disrup-
tion and ACS.
Role in Atherogenesis and Plaque
Destabilization
Matrix metalloproteinases are a group of protei-
nases consisting of 23 structurally related mem-
bers that degrade fibrillar collagen type I and III,
proteoglycans, collagen, and elastin, which are all
ATHEROSCLEROTIC PLAQUE STABILITY
substantial constituents of the fibrous athero-
sclerotic cap.19 Experimental evidence in mouse
models suggests that degradation of ECM by
MMPs plays an important role not only in plaque
destabilization as discussed above, but also in
myocardial rupture,22 which is a life-threatening
complication of MI. Recently, van den Borne et
al23 showed that tissue samples from the left
ventricle of a patient who died of acute infract
rupture exhibited significantly higher levels of
both latent and activated MMP-8 and MMP-9 than
tissue samples from nonruptured MI.
In addition to their effects on matrix degrada-
tion, MMPs could also be involved in triggering of
ACS by their ability to promote platelet activation.
Thus, MMP-1 is located at the plasma membrane
of platelets where it modifies αIIβ3 integrin,
thereby inducing intracellular tyrosine phosphor-
ylation events and priming platelets for aggrega-
tion.24 In addition, MMP-2 has been localized to
the cytosolic compartment of human platelets and
is translocated to the platelet surface and released
during platelet aggregation.25 Matrix metallopro-
teinase 2 also potentiates the von Willebrand–
mediated induction of GPIb expression and
platelet adhesion.26 Similarly, MMP-2 amplifies
the pro-aggregatory effects of collagen on platelets
through a mechanism thought to be independent
of aspirin and thromboxane.27 The combined
effects on matrix degradation and platelet activa-
tion further suggest an important role for MMPs
in the triggering of ACS. This notion has also been
supported by in vivo studies showing that plasma
levels of MMPs are able to prognosticate future
coronary events. In particular, Blankenberg et al28
reported a strong and independent association
between plasma levels of MMP-9 and subsequent
4.1-year risk for fatal CAD events among 1127
subjects with established coronary disease. This
association was independent of conventional
cardiovascular risk factors.28
However, the effect of MMPs on atherogenesis
is rather complex. Thus, MMP-1 overexpression
in macrophages has been found to reduce the
progression of atherosclerosis in apoE−/− mice,
because it resulted in less collagenous matrix
accumulation, but there were no data on plaque
stability for these animals.29 In fact, MMP-3
deficiency has been associated with increased
collagen content in the plaques of apoE−/− mice,30
which is consistent with greater stability, although
187
plaque size was increased overall, illustrating the
dual role of MMPs in atherogenesis (ie, attenuat-
ing atherosclerosis and promoting plaque desta-
bilization). On the other hand, MMP-2–deficient
apoE–/– mice showed a significant reduction of the
overall atherosclerosis, 31 suggesting that the
effects on atherosclerosis may differ between
MMP-1 and MMP-2. Furthermore, Dean et al32
reported a new and intriguing function of
macrophages and MMP-12. The authors showed
that macrophage-specific MMP-12 truncated and
inactivated leukocyte-derived CXC chemokines
(ie, CXCL 1, 2, 3, 5, and 8) and monocyte
chemotactic proteins like CCL2, -7, -8, and -13.32
These data suggest that MMP-12 has anti- rather
than pro-atherogenic property. Finally, VSMCs
may also have a dual role in atherosclerosis and
plaque destabilization. Vascular smooth muscle
cells secrete and deposit ECM proteins and are
therefore considered protective against athero-
sclerotic plaque destabilization. However, similar
to inflammatory cells (eg, macrophages), VSMCs
can release numerous MMPs that are capable of
digesting ECM proteins. In fact, the transition of
VSMCs from a migrating to a secretory phenotype
is an important event in plaque destabilization,
potentially involving dual interactions between
MMPs and VSMCs. The interaction between
VSMCs and matrix-degrading enzymes, as well
as the different roles of MMPs in atherogenesis
and plaque destabilization, is complex and not
fully understood, and further studies of these
processes are an important goal for future research
in this area.
Apoptosis Decreases Cellularity but
Enhances the Vulnerability of
Atherosclerotic Plaques
Although the pathologic and clinical significance
of apoptosis in atherosclerosis remains unclear, it
has recently been proposed that apoptotic cell
death may contribute to plaque instability, rup-
ture, and thrombus formation,33,34 and that the
immune system may be involved in this process.35
First, inflammatory mediators may participate in
endothelial cell denudation by promoting cyto-
kine-induced endothelial apoptosis. 34 Indeed,
serum from patients with ACS was recently
found to trigger apoptosis in human endothelial
cells,36 supporting the theory that circulating
188
mediators may also cause plaque disruption.
Second, although apoptosis of macrophages has
been thought to be beneficial by removal of
inflammatory cells from the plaque, inhibition of
apoptosis induced by ischemia reperfusion was
recently shown to prevent inflammation in a
murine model37 challenging the concept of anti-
inflammatory effects of apoptosis in vascular
disorders. A link between apoptosis and inflam-
mation during atherogenesis is further supported
by the observation that apoptosis in athero-
sclerotic plaques is associated with the accumu-
lation of inflammatory cells such as T cells and
monocytes with the potential to release inflam-
matory cytokines with proapoptotic properties
(eg, TNF-α and IL-1β). Third, although apopto-
tic macrophages in fatty streaks are rare,
macrophage and foam cell apoptosis is a
prominent feature in advanced atherosclerotic
plaques, promoting the formation of a necrotic
core that may contribute to plaque destabiliza-
tion.38 In fact, reduction in macrophage apop-
tosis has been shown to account for the
decreased formation of necrotic cores in some
animal models of atherosclerosis38 and, interest-
ingly, such a phenomenon was recently observed
in low-density lipoprotein receptor–null mice
overexpressing the anti-inflammatory cytokine
IL-10.39 Our recent demonstration of an anti-
apoptotic effect of IL-10 in foam cell macro-
phages further supports a role for the link
between IL-10 and decreased macrophage apop-
tosis during atherogenesis.40
Particular attention has been drawn toward the
role of VSMC apoptosis in atherogenesis. 41
Apoptosis of VSMCs may weaken the plaque by
decreasing the number of collagen-synthesizing
cells within the atherosclerotic lesion. Moreover,
rapid exposure of membrane phosphatidylserine
and loss of the anticoagulant membrane compo-
nents in apoptotic VSMCs create a procoagulant
environment.42 Vascular smooth muscle cell
apoptosis may also cause release of inflammatory
cytokines such as IL-1α, IL-8, and MCP-1, which
in turn causes macrophage recruitment into the
lesions.43 Actually, it has been suggested that
induction of an inflammatory program by
apoptotic VSMCs may contribute to the patho-
genesis of vascular disease, including destabiliza-
tion of atherosclerotic plaques. Clarke et al44
recently showed that the direct consequence of
HALVORSEN ET AL
VSMC apoptosis was a feature of plaque vulner-
ability in already established atherosclerosis. The
demonstration of an association between VSMC
death rate and the degree of plaque instability
further supports the role of VSMC apoptosis in
plaque destabilization.33,34
Several mediators and pathways may be
involved in the regulation of apoptosis within
an atherosclerotic lesion. First, the balance
between MMPs and their endogenous tissue
inhibitors (tissue inhibitor of metalloprotei-
nases) seems to be important in plaque devel-
opment not only through matrix breakdown,
but also through their ability to modulate cell
survival. Thus, tissue inhibitor of metalloprotei-
nase-3 has been found to induce apoptosis in
VSMCs by inhibiting an MMP-mediated down-
regulation of TNF receptor on the cellular
surface.45,46 Second, several members of the
TNF superfamily may promote apoptosis in
various cell types with relevance to athero-
sclerosis. Thus, Fas has been reported to
promote VSMC apoptosis through interaction
between Fas ligand on infiltrating T cells and
macrophages and Fas expressing VSMCs, which
in contrast to its ligand is ubiquitously
expressed on a wide range of cells.47-49 Third,
p53 is a transcription factor that is found to
accumulate in atherosclerotic lesions.50 Interest-
ingly, p53 can promote VSMC apoptosis by
promoting Fas-mediated apoptosis,51 and, in
vivo, p53 deficiency has been found to exacer-
bate atherosclerotic lesion expansion in ApoE-
deficient mice fed with high-fat diet.52 Finally,
enhanced oxidative stress at least partly through
mitochondrial-dependent mechanisms may also
promote apoptosis of VSMCs and macrophages
within an atherosclerotic lesion.
Thus, although the role of apoptosis in
plaque destabilization and the involvement of
inflammatory cytokines in this form of athero-
sclerotic cell death will have to be further
elucidated, therapeutic intervention aiming to
inhibit endothelial cell, foam cell, and VSMC
apoptosis may be an interesting plaque-stabiliz-
ing approach in CAD. However, it is important
to underscore that, although enhanced apopto-
sis may be harmful in vulnerable lesions,
increased apoptosis may be beneficial in the
early stage of atherosclerosis through inhibition
of lesion formation.
ATHEROSCLEROTIC PLAQUE STABILITY
Macrophages: A Key Regulator of MMP
Activity, Apoptosis, and
Thrombus Formation
Plaque vulnerability is a primary determinant of
thrombus and rupture-mediated complications. In
women older than 50 years, 80% of all coronary
thrombi occur from plaque rupture.8 In this
regard, macrophages play vital roles in vascular
remodeling and plaque destabilization through
the production of various enzymes, activators,
inhibitors, and bioactive mediators, and, impor-
tantly, macrophages are more abundant in lesions
featuring intense inflammatory responses and
vulnerable plaques. Several nonmutually exclu-
sive mechanisms may contribute to the role of
macrophages in plaque destabilization. First, as
discussed above, macrophages are a major cellular
source of MMPs within the atherosclerotic
lesion.53-55 Macrophage infiltration and expres-
sion of MMP-9 are markers of high-risk athero-
sclerotic carotid plaque and strong indicators of
plaque instability.21 Besides MMP-9, we have
found that MMP-1 and MMP-12 are significantly
increased in carotid plaques from patients with
unstable carotid disease, as compared to those
patients with stable disease (unpublished data, B.
Halvorsen, M. Skjelland, and P. Aukrust). Thus,
activation of macrophages by various inflamma-
tory cytokines that are abundant within an
unstable lesion results in a marked increase in
expression and release of MMPs such as MMP-1,
MMP-2, MMP-9, MMP-12, and MMP-13, con-
tributing to degradation of the stabilizing
matrix.56 Second, vulnerable plaques are charac-
terized by accumulation of considerable apoptotic
cells,43,44,57 especially apoptotic macrophages and
VSMCs, and macrophages could contribute to this
process by enhanced production of nitric oxide
and proapoptotic mediators such as Fas.58 Oxi-
dized low-density lipoprotein–mediated macro-
phage apoptosis could also promote plaque
destabilization, and IL-10 has recently been
shown to counteract this process by upregulating
the antiapoptotic genes Mcl-1 and Bfl-1.40 Third,
macrophages could promote ACS by upregulating
tissue factor and plasminogen activator inhibitor
1, and downregulating the antithrombotic med-
iator thrombomodulin. In fact, we have recently
shown that the TNF superfamily member LIGHT
(lymphotoxin-like, exhibits inducible expression,
189
and competes with HSV glycoprotein D for
HVEM, a receptor expressed by T lymphocytes)
transforms foam cell macrophages into a pro-
thrombotic, inflammatory, and matrix-degrading
phenotype, and, notably, patients with ACS are
characterized by increased serum levels of
LIGHT.59 Finally, microbial antigens and heat
shock proteins seem to be involved in triggering of
ACS and plaque rupture, and through interaction
with toll-like receptors or various scavenger
receptors on macrophages, these cells could play
a key role in this inflammatory interaction.60
T. Helper Type 1: An Important
Inflammatory Actor in
Plaque Destabilization
In view of the complexity of T-cell subsets and
activities, it has been suggested that only subsets
of T cells account for their proatherogenic activity.
Recently, Zhou et al showed that the absence of
CD4+ cells in apoE–/– mice leads to reduced
atherosclerosis, indicating that CD4+ T cells
constitute a major proatherogenic cell popula-
tion. 61 There is solid evidence from several
independent groups that the T helper type 1
(Th1) subset is a particular proatherogenic subset
within the CD4+ T-cell population. First, a
number of studies have colocalized CD4+ T cells
and IFN-γ within human and mouse athero-
sclerotic lesions, suggesting the predominance of
Th1 cells in atherogenesis.62,63 More recently,
high levels of IL-12 and IL-18 mRNA and protein
have also been detected in atherosclerotic plaques
further suggesting a Th1 profile in these lesions.64
Second, a direct role in atherogenesis has been
defined in atherosclerotic-susceptible mice that
are deficient in either IFN-γ receptors or the
cytokine itself. Conversely, injection of IFN-γ or
the IFN-γ–releasing factors IL-12 and IL-18
enhances the extent of disease in apoE –/–
mice.65 Finally, monocytes from patients with
unstable angina exhibit a molecular fingerprint of
a recent IFN-γ triggering. Such patients also have
raised plasma levels of IL-18, significantly corre-
lated with the degree of myocardial dysfunction,
further implicating Th1-mediated immune
responses in the pathogenesis of ACS.66 The
proposed pathogenic role of Th1-derived IFNγ is
partly related to its ability to enhance recruitment
of T cells and macrophages to the plaques, to
190
increase macrophage uptake of lipids leading to
the formation of foam cells (5 ), to increase
activation of antigen-presenting cells, and to
further enhance the secretion of Th1-promoting
cytokines which subsequently continues to drive
these processes acting as a self-perpetuating
pathogenic loop in atherogenesis and plaque
destabilization (reviewed by Aukrust et al67).
However, the pathogenic role of IFN-γ is not only
dependent on its ability to induce immune
activation and inflammation. In fact, through its
capacity to prevent infiltration and proliferation
of VSMCs as well as to reduce collagen synthesis,
to attenuate production of ECM, and to enhance
MMP activity, IFN-γ may promote plaque desta-
bilization and plaque rupture through thinning or
inhibition of formation of the fibrous cap.
CD8 + T Cells: Proapoptotic Mediator
During Plaque Destabilization
Although several lines of evidence suggest the
involvement of CD8+ T cells in tissue destruction in
various autoimmune disorders, little data exist
regarding the precise role of CD8+ T cells in
atherogenesis.4 However, through their ability to
release large amount of granzyme B upon activa-
tion, these T cells may promote vascular SMC
apoptosis and plaque destabilization within an
atherosclerotic lesion. Our recent finding of
increased serum levels of granzyme B in echolucent
as compared with echogenic carotid plaque68 may
further support such a notion. Moreover, Olofsson
et al69 have recently shown that activation of 4-1BB,
a member of the TNF receptor superfamily, in
apoE–/– mice promoted an inflammatory lesion at
least partly involving enhanced infiltration of CD8+
T cells. These studies may suggest that CD8+ T cells
could also be involved in atherogenesis and plaque
destabilization at least partly through their ability to
promote apoptosis with the atherosclerotic lesion.
Platelets and Inflammation—Pathogenic
Loop During Plaque Destabilization
Blood platelets play a critical role in hemostasis,
providing rapid protection against bleeding and
catalyzing the formation of stable blood clots via the
coagulation cascade.70 Recently, activated platelets
have been implicated not only in thrombosis, but
also in inflammatory reactions, immune responses,
HALVORSEN ET AL
and in distinct aspects of atherosclerosis.71 Thus,
several studies suggest a role for platelets as
inflammatory cells.72-74 First, platelets provide a
wide range of growth factors and inflammatory
mediators by their release from intracellular storage
organelles. Included in this group of mediators are
several members of the chemokine family, IL-7, and
members of the TNF superfamily such as soluble
CD40 ligand and LIGHT. Second, platelets do not
only contain and express inflammatory mediators,
but may upon activation also induce the expression
of such substances (eg, TNF-α and chemokines) in
monocytes/macrophages, granulocytes, and
endothelial cells.72,75,76 Actually, upon activation
platelets express P-selectin on their surface.
Through ligation with its counterpart on mono-
cytes/macrophages, P-selectin has the potential to
enhance the activation of nuclear factor κB,77 a
transcription factor required for chemokines, TNF-
α, and several other gene products playing a key
role in inflammation. We have recently shown that
platelet-derived prostaglandin E2 could also con-
tribute to this platelet-mediated activation of
monocytes.78 Moreover, platelet-derived LIGHT
has recently been found to enhance the inflamma-
tory and prothrombotic potential of endothelial
cells, and, notably, immunostaining of thrombus
material obtained at the site of plaque rupture in MI
patients suggests that such LIGHT-mediated
mechanisms could be operating in vivo during
plaque destabilization.79 Finally, platelets may also
themselves respond to inflammatory mediators
produced by these cells. In fact, platelets have
recently been found to express several chemokine
receptors that upon stimulation endorse platelet
activation.80,81 Thus, during activation platelets
may release and express inflammatory mediators,
induce an inflammatory response within leukocytes
and endothelial cells, and respond with activation
to several of the inflammatory mediators produced
by these cells. We and others have suggested that
this inflammatory interaction between platelets and
other cells may represent a vicious cycle playing a
pathogenic role in triggering of the ACS.72,79,82
Mast Cells: A New Mediator in
Plaque Destabilization
Mast cells have recently been shown participate in
the inflammatory infiltrates of human atherosclero-
tic lesions.83 These cells contribute importantly to
ATHEROSCLEROTIC PLAQUE STABILITY
allergic and innate immune responses by releasing a
wide range of mediators. Pathologic examinations
have revealed that mast cells are located at site
rupture.84 Interestingly, MMP-12 is macrophage-
specific MMP,55 whereas MMP-1 is produced both
by macrophages85,86 and mast cells,87 and both
these MMPs have been found to be located in the
shoulder region of the plaque, suggesting the
involvement of both these cell types during plaque
rupture. Recently, Sun et al88 reported evidence for
direct participations of mast cells in an athero-
sclerotic mice model. The author found that mast
cell–derived IL-6 and IFN-γ promoted athero-
sclerosis by augmenting the expression of MMPs,
and recent studies have shown that mast cells are an
important cellular source of TNF-α, a prototypic
inflammatory cytokine with a marked MMP-indu-
cing potential. Moreover, mast cells produce large
amounts of serine proteinases like tryptase and
chymase, which activate the MMP pro-enzymes.89
These data indicate the total burden of proteinases
produced by mast cells and their capability to cause
damages to the fibrous cap.
Mast cell activation may also contribute to
apoptosis. The mast cell–derived chymase is
reported to activate caspase-8 and caspase-9, 2
key effector molecules in apoptotic cascade.90 As
activated mast cells can induce endothelial cell
apoptosis91 and are colocalized with apoptotic
VSMCs in vulnerable areas of human athero-
sclerotic plaques,90 they may actively participate
in the weakening and rupture of atherosclerotic
plaques both through MMP production and by
provoking apoptosis.
Mast cells can also elaborate autacoids, such as
histamine, and numerous lipid mediators includ-
ing prostanoids and leukotrienes, that may aug-
ment vascular permeability and alter vascular tone,
as well as promote inflammatory responses.92 In
addition to MMPs, mast cell chymase can activate
angiotensin I and thus function as an angiotensin-
converting enzyme important in regulating vas-
cular tone,93 oxidative stress, and inflammatory
responses of vascular wall cells.88,94 When they
degranulate, mast cells can release heparin that can
bind growth-regulatory proteins, activate antith-
rombin III, and influence lipolysis through well-
explored pathways.95 Thus, mast cells exhibit a
panoply of functions that might modulate ather-
ogenesis and plaque destabilization that should be
further explored in the coming years.
191
Conclusion
Our understanding of the mechanisms underlying
atherosclerosis has evolved beyond the view that
this disease reflects progressive collection of lipids
and cellular debris in the vascular wall. It is now
evident that physical disruption of atherosclerotic
plaques (ie, endothelial erosions and fibrous cap
rupture) with subsequent thrombus formation
and vascular obstruction is a dominant mechanism
for acute coronary events. Substantial biological
data have implicated the role of inflammatory
pathways in the pathogenesis of this process. New
inflammatory mediators such as members of the
TNF superfamily seem to contribute substan-
tially to the progression of atherosclerotic devel-
opment. Other inflammatory cytokines attenuate
interstitial collagen synthesis, increase matrix
degradation, and promote apoptosis in several
atheroma-associated cell types—all cellular
events that may cause plaque rupture. Treatment
modalities that counteract atherothrombotic pro-
cesses such as apoptosis and matrix degradation
will certainly be potential targets for future
therapy in high-risk individuals.
Acknowledgments
This work was supported by grants from the
Norwegian Council of Cardiovascular Research,
The University of Oslo, Rikshospitalet Medical
Center, and Helse Sør-Øst.
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