C-Reactive Protein is a Vasoreactive
Subodh Verma, M.D., Ph.D.
Division of Cardiac Surgery
University of Toronto, Toronto, ON, Canada
VP Watch – October 9, 2002 - Volume 2, Issue 40
Inflammation is now considered to be at
the root of atherosclerosis.1,2
Markers of inflammation, such as
C-Reactive Protein (CRP), have been
demonstrated to be associated with the
development of atherosclerosis and
Inflammation and Atherosclerosis
CRP has been shown to predict the
development of future cardiovascular disease.5,6
Recently CRP has been found to be localized in
atherosclerotic plaques and induces the
expression of proatherogenic cell adhesion
molecules, cytokines such as MCP-1 and IL-6,
and vasoreactive substances such as ET-1.7,8
CRP also has been found to decrease
endothelial NO synthesis which results in
C-Reactive Protein and Atherosclerosis
Elevated CRP is associated with blunted
systemic endothelial vasodilator function in
addition to endothelial dysfunction present in
acute coronary syndromes.10,11
Fichtlscherer et al. were able to demonstrate
an inverse relationship between endothelium-
dependent blood flow responses and CRP
serum levels in patients with CAD.10
CRP and Vasoreactivity
Fichtlscherer et al. measured endothelium-dependent forearm blood flow responses with
venous plethysmography in patients with angiographically documented CAD. Endothelium-
dependent forearem blood flow responses were inversely correlated to CRP serum leves.10
CRP and Endothelium-Dependent Vasoreactivity
Cleland et al.
chronic low grade
by CRP levels) and
endothelial NO synthesis
as an indicator of
Their results indicated,
for the first time, that
elevated CRP is
NO synthesis as
indicated by blood flow
responses to L-NMMA. 12
Endothelial dysfunction and CRP
• These two studies both clearly demonstrate
that CRP is associated with endothelial
dysfunction and but do not tell us anything
about any potential s direct effect CRP has
As reported in VP Watch of this week,
Sternik et al. show for the first time the potent
direct vasodilatory effect of CRP on human
internal mammary artery segments.13
Organ bath experiments were utilized to
assess the vasoreactive effect of varying
concentrations of CRP on precontracted (with
ET-1) IMA segments.13
They showed that CRP was able to
vasodilate human IMA in a dose-dependent
manner and that this response was not
attenuated by the removal of the endothelium.
Further experiments demonstrated that this
vasorelaxatory response to CRP is NO
independent, since incubation with L-NMMA, an
inhibitor of NO synthase, did not attenute this
Vasorelaxation Response of IMAs to CRP
Leonid Sternik, Saquib Samee, Hartzel V. Schaff, Kenton J. Zehr, Lilach O. Lerman, David R. Holmes, Joerg Herrmann, Amir Lerman; C-Reactive
Protein Relaxes Human Vessels In Vitro Arteriocler Thromb Vasc Biol. 2002 22: ??? - ???
-10.5 -10 -9.5 -9 -8.5 -8 -7.5 -7 -6.5 -6
CRP [log mol/L]
IMA IMA E-
Since hyperpolarization of VSMCs in
response to activation of potassium channels
has been identifed as an important mechanism
of vasodilation, Sternik et al. investigated the
role of K+
channels in CRP inducted
Their results obtained using preincubation
with varying concentration of KCl as well as the
channel inhibitors, BaCl and TEA indicate the
Potassium Channels are mediators of CRP’s
vasorelaxing effect on IMA segments.
C-Reactive Protein has a direct
This response is mediated, at least in
part, through potassium channels on
vascular smooth muscle cells.
This study provides important evidence
supporting the theory that CRP is more
than just a marker of inflammation and
is likely a key direct participant in the
chronic inflammatory process
associated with atherosclerosis.
• Does CRP act directly on VSMCs or is
their an intermediate signalling
molecule such as ET-1 involved in
• Are there pharmacologic agents such
as ET-1 receptor antagonists
(Bosentan) that blunt CRP’s effect on
• Does CRP induced vasorelaxation play
a role in development of long-term
atherosclerosis and plaque formation?
• Is CRP more of a trigger that causes
plaque instability or vulnerable plaque
resulting in rupture and thrombosis?
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2) Libby P. Atherosclerosis: The New View. Sci Am 2002;286:46-55.
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