Paul E Szmitko

Subodh Verma

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Clinical Science (2005) 108, 493–495 (Printed in Great Britain) 493
C O M M E N T
C-reactive protein and statins:
IL-8 as a molecular link?
Paul E. SZMITKO∗ and Subodh VERMA†
∗Division of General Internal Medicine, University of Toronto, Ontario, Canada, and †Division of Cardiac Surgery,
St. Michael’s Hospital, Toronto, Ontario, Canada
A B S T R A C T
CRP (C-reactive protein) has not only emerged as a useful biomarker for cardiovascular disease,
but also as a mediator of atherosclerosis. CRP directly activates vascular endothelial cells, ampli-
fying the inflammatory response underlying atherogenesis. The expression of IL (interleukin)-8
appears to serve as one of the downstream effects of CRP. Kibayashi and co-workers in this
issue of Clinical Science confirm that CRP induces IL-8 production in human aortic endothelial
cells in vitro, via the activation of MAPKs (mitogen-activated protein kinases), an effect that can be
inhibited by pitavastatin.
Atherosclerosis is currently regarded as a dynamic and
progressive disease arising from the combination of endo-
thelial dysfunction and inflammation [1]. Impairing vas-
cular homoeostasis makes the vasculature susceptible to
atheroma formation. CRP (C-reactive protein), formerly
regarded as solely a biomarker for inflammation, is cur-
rently regarded as a prominent partaker in endothelial
dysfunction and atherosclerosis [2].
With the advent of high-sensitivity assays, CRP has
emerged as one of the most powerful independent pre-
dictors of cardiovascular disease, prompting the Centers
for Disease Control and Prevention and the American
Heart Association to issue a class IIa recommend-
ation for its measurement as a routine part of global
cardiovascular risk assessment [3]. However, as an active
partaker in atherosclerosis, the molecular effects of
excessive CRP action on the vasculature may serve as
targets for therapeutic intervention. In this issue of
Clinical Science, Kibayashi et al. [4] suggest that the
proatherosclerotic effects of CRP upon the endothelium
involve the production of IL-8, an action that is sup-
pressed by pitavastatin.
Human recombinant CRP has been demonstrated
to elicit a multitude of effects on endothelial biology
favouring a proinflammatory and proatherosclerotic
phenotype [1,2]. In vitro experiments reveal that CRP
potently down-regulates eNOS [endothelial NO (nitric
oxide) synthase] transcription and destabilizes eNOS
mRNA, resulting in decreased basal and stimulated NO
release. In a synchronous fashion, CRP stimulates ET-1
(endothelin-1) and IL (interleukin)-6 release from endo-
thelial cells, and decreases the production of the potent
vasodilator prostacyclin, shifting the balance towards
endothelial dysfunction. By up-regulating the expression
of adhesion molecules such as ICAM-1 (intercellular cell-
adhesion molecule 1), VCAM-1 (vascular cell adhesion
molecule-1) and E-selectin, and stimulating the release of
MCP-1 (monocyte chemotactic protein-1), a chemokine
which facilitates leucocyte transmigration, plaque pro-
gression is enhanced. Furthermore, CRP potently up-
regulates NF-κB (nuclear factor κB) [5], a key nuclear
factor that facilitates the transcription of numerous
proatherosclerotic genes, and inhibits bone-marrow-
derived EPC (endothelial progenitor cell) survival and
Key words: atherosclerosis, C-reactive protein (CRP), interleukin-8, mitogen-activated protein kinase (MAPK), 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) reductase inhibitor, statin.
Abbreviations: apoE, apolipoprotein E; AT1-R, angiotensin type 1 receptor; CRP-tg, CRP transgene; EPC, endothelial progenitor
cell; ERK, extracellular signal-regulated kinase; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; IL, interleukin; JNK, c-Jun
N-terminal kinase; LDL, low-density lipoprotein; MAPK, mitogen-activated protein kinase; mCRP, monomeric CRP; NO, nitric
oxide; eNOS, endothelial NO synthase; VCAM-1, vascular cell adhesion molecule-1.
Correspondence: Dr Subodh Verma (email subodh.verma@sympatico.ca).
C© 2005 The Biochemical Society
494 Comment
differentiation [6]. EPCs have been suggested to play
an important role in postnatal neovascularization, and
the ability of CRP to inhibit progenitor cells may be
an important mechanism inhibiting compensatory angio-
genesis in chronic ischaemia [7]. CRP also has direct
proatherogenic effects in vascular smooth muscle cells,
directly up-regulating AT1-R (angiotensin type 1 re-
ceptor), which stimulates vascular smooth muscle migra-
tion, proliferation, neointimal formation and reactive
oxygen species production [8]. Finally, CRP plays a role
in the destabilization of the atheroma’s fibrous cap by
stimulating MMP-1 (matrix metalloproteinase-1) release
[9] and impairing fibrinolysis by promoting the synthesis
of PAI-1 (plasminogen activator inhibitor-1) [10]. Recent
work has revealed that, in order for CRP to promote this
proinflammatory phenotype, native pentametric CRP
must undergo structural modification, forming active
monomeric subunits [11]. Furthermore, the exact nature
of the CRP receptor on endothelial cells is unknown, and
may be distinct for native and mCRP (monomeric CRP),
with the possible involvement of Fcγ RII and Fcγ RIII
(where Fcγ R is Fcγ receptor) respectively [11]. Further
elucidation of this molecular interaction may serve to
uncover novel therapeutic targets.
These in vitro results were confirmed in vivo in
human CRP transgenic mice. First, human CRP creates
a prothrombotic phenotype, as evidenced by higher rates
of thrombotic occlusion following arterial injury [12].
Secondly, by crossing CRP-tg (CRP transgene) mice with
the atherosclerosis prone apoE (apolipoprotein E)−/−
mice, CRP was shown to be an active player in
atherogenesis in vivo ([13], but see [13a]). These CRP-
tg/apoE−/− mice displayed accelerated aortic atheroscler-
osis, which was associated with increased complement
deposition and elevated expression of AT1-R, VCAM-1
and collagen within the lesions. However, CRP also ap-
pears to up-regulate complement-inhibitory proteins and
protects endothelial cells from complement-mediated cell
injury [14], suggesting that a balance of proatherogenic
and antiatherogenic effects of CRP on the vessel wall may
be important in the development of atherosclerosis. The
present study by Kibayashi et al. [4] suggests that CRP-
mediated production of IL-8 may be added to the list of
the detrimental vascular effects of CRP. IL-8, a member
of the CXC chemokines, promotes monocyte–endo-
thelial cell adhesion and arrest and is abundant in athero-
sclerotic plaques. Although CRP induced IL-8 secretion
in human aortic endothelial cells has been reported prev-
iously [11,15] and the activation of p38 MAPK (mitogen-
activated protein kinase) was implicated [11], Kibayashi
et al. [4] show that the CRP-induced production of IL-
8 was dependent on not only p38 MAPK, but also on
two other signalling pathways, the ERK (extracellular
signal-regulated kinase) and JNK (c-Jun N-terminal
kinase) pathways. The MAPKs are signalling pathways
which participate in the inflammatory response and have
been implicated in the production and stabilization of
cytokines and chemokines, and in cardiomyocyte death
following ischaemia/reperfusion injury. CRP-induced
activation of these pathways has been linked to several
of the other less favourable vascular effects observed
in in vitro studies and, probably, several additional
molecular pathways will be implicated in mediating the
harmful effects of CRP. Recently, p38 MAPK activation
was demonstrated to impair endothelium-dependent
NO-mediated vasoreactivity [16] and to have a detri-
mental effect on EPC number and capacity for neovascu-
larization [17]. Nevertheless, Kibayashi et al. [4],
demonstrate further that pitavastatin, an HMG-CoA
(3-hydroxy-3-methylglutaryl-CoA) reductase inhibitor,
inhibits IL-8 mRNA expression induced by CRP in
human aortic endothelial cells through the inhibition of
the three MAPK pathways. Thus it appears that statins
may directly inhibit the cellular effects of CRP in addition
to the clinically observed statin-mediated reduction in
circulating CRP levels.
HMG-CoA reductase inhibitors, commonly referred
to as statins, have emerged as an effective means of redu-
cing the risk for cardiovascular disease. Statins have been
demonstrated to significantly reduce cardiovascular risk
in several large randomized controlled trials conducted in
both primary and secondary prevention settings, beyond
their effect on lipids. One of these additional non-lipid
effects was believed to be an anti-inflammatory effect,
involving the reduction of circulating CRP levels, which
served to enhance endothelial function and subsequently
impair atherogenesis.
Statin therapy was shown to reduce the level of CRP
independently of its effect on lipid levels in analyses of the
AFCAPS/TexCAPS (Air Force/Texas Coronary Ather-
osclerosis Prevention Study), the PRINCE (Pravastatin
Inflammation CRP Evaluation) and the REVERSAL
(Reversal of Atherosclerosis with Aggressive Lipid
Lowering) trials. Furthermore, patients who have lower
CRP levels after statin therapy have better clinical out-
comes, including reduced rates of atherosclerosis pro-
gression, than those with higher CRP levels, regardless
of the LDL (low-density lipoprotein)-cholesterol level
[18,19]. This suggests that CRP lowering may be a target
for intervention and that CRP should be monitored in
addition to LDL-cholesterol to assess the effectiveness
of statin therapy. Despite the apparent clinical data
supporting the role of CRP as not only a biomarker, but
also as a proatherosclerotic molecule, and the apparent
reduction in CRP levels with statin therapy, no direct
evidence linking the sole lowering of CRP level to overall
survival currently exists. To partially address this concern,
the JUPITER trial (Justification of the Use of statins
in Primary prevention: an Intervention Trial Evaluating
Rosuvastatin) is currently being conducted [20].
However, as the current study by Kibayashi et al. [4]
suggests, the favourable pleiotropic effects of statins may
C© 2005 The Biochemical Society
Comment 495
involve more than just a reduction in circulating CRP
levels, but may also negate the effects of CRP at the
cellular level. Thus statins may serve a dual purpose.
First, they may provide a systemic anti-inflammatory
effect, and secondly, they may directly act at the tissue
level inhibiting the CRP-mediated molecular pathways
responsible for atherogenesis. However, it would be
naı̈ve to assume that blocking IL-8 activity alone
would completely negate the detrimental effects of CRP.
The inhibitory effect of pitavastatin on the MAPKs
would probably extend to a promotion of NO release,
favourable effects on EPC biology and a reduction in
other markers of endothelial activation such as adhesion
molecule expression. However, these other potential
downstream consequences of CRP activity were not
assessed in the present study by Kibayashi et al. [4].
Furthermore, the results may have been different had
mCRP been employed. Since it appears that pentameric
CRP must undergo a conformational change to mCRP
to exert its activity [11], the relatively short CRP
cell treatment times employed by Kibayashi et al. [4]
(4 h) may not have allowed for the maximal effect of
CRP to be obtained. Thus the positive results observed
with pitavastatin treatment may be overestimated. Also,
whether the inhibition of the MAPKs is unique to
pitavastatin or represents a class effect remains to be
determined. Finally, as with every in vitro study, will
the observed results be replicated in vivo and, of more
importance, will treatment with pitavastatin result in
any noticeable clinical benefit? The present work by
Kibayashi et al. [4] reveals some of the molecular links
explaining the beneficial effect of statins on limiting the
negative effects of CRP. However, several more molecular
pieces undoubtedly remain before the entire statin–CRP
story is revealed.
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Received 15 March 2005/22 March 2005; accepted 30 March 2005
Published as Immediate Publication 30 March 2005, DOI 10.1042/CS20050093
C© 2005 The Biochemical Society


C-reactive protein and statins: IL-8 as a molecular link?

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C-reactive protein and statins: IL-8 as a molecular link?

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