This document discusses recent research findings about C-Reactive Protein (CRP) and its relationship to atherosclerosis and cardiovascular disease. Specifically, it summarizes studies that have found CRP has a direct vasodilatory effect on blood vessels through activation of potassium channels on vascular smooth muscle cells. This represents an important finding as it suggests CRP is actively involved in chronic inflammation associated with atherosclerosis, rather than just being a marker of inflammation. Questions are also posed about the mechanisms and implications of this vasodilatory effect.

1. C-Reactive Protein is a Vasoreactive
Substance?!
Provided by:
Subodh Verma, M.D., Ph.D.
Division of Cardiac Surgery
University of Toronto, Toronto, ON, Canada
Editorial Slides
VP Watch – October 9, 2002 - Volume 2, Issue 40

2.  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
cardiovascular disease.3,4
Inflammation and Atherosclerosis

3.  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
endothelial dysfunction.9
C-Reactive Protein and Atherosclerosis

4.  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

5.  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

6.  Cleland et al.
investigated the
relationship between
chronic low grade
inflammation (indicated
by CRP levels) and
endothelial NO synthesis
as an indicator of
endothelial function.12
 Their results indicated,
for the first time, that
elevated CRP is
associated with
decreased endothelial
NO synthesis as
indicated by blood flow
responses to L-NMMA. 12
Endothelial dysfunction and CRP

7. • 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
on vasoreactivity…

8.  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

9.  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
vasodilatory response.
Results

10. 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: ??? - ???
0
10
20
30
40
50
60
70
80
90
100
-10.5 -10 -9.5 -9 -8.5 -8 -7.5 -7 -6.5 -6
CRP [log mol/L]
%Relaxation
IMA IMA E-

11.  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
vasodilation.
 Their results obtained using preincubation
with varying concentration of KCl as well as the
K+
channel inhibitors, BaCl and TEA indicate the
Potassium Channels are mediators of CRP’s
vasorelaxing effect on IMA segments.
Results

12. Conclusion:
 C-Reactive Protein has a direct
endothelium-independent vasodilatory
effect.
 This response is mediated, at least in
part, through potassium channels on
vascular smooth muscle cells.

13. Conclusion:
 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.

14. Questions:
• Does CRP act directly on VSMCs or is
their an intermediate signalling
molecule such as ET-1 involved in
autocrine/paracrine signalling?
• Are there pharmacologic agents such
as ET-1 receptor antagonists
(Bosentan) that blunt CRP’s effect on
vasorelaxation?

15. Questions:
• 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?

16. 1) Libby P, Ridker PM, Maseri A. Inflammation and Atherosclerosis. Circulation 2002;105:1135-1143.
2) Libby P. Atherosclerosis: The New View. Sci Am 2002;286:46-55.
3) Saadeddin SM, Habbab MA, Ferns GA. Markers of Inflammation and Coronary Artery Disease. Med Sci Monit
2002;8:RA5-12.
4) Rader DJ. Inflammatory Markers of Coronary Risk. N Engl J Med 2000;343:1179-1182.
5) Rifai N, Ridker PM. High-Sensitivity C-Reactive Protein: A Novel and Promising Marker of Coronary Heart
Disease. Clin Chem 2001;47:403-411.
6) Kushner I. C-Reactive Protein and Atherosclerosis. Science 2002;297:520-521.
7) Pasceri V, Willerson JT, Yeh ET. Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial
Cells. Circulation 2000;102:2165-2168.
8) Verma S, Li SH, Badiwala MV, Weisel RD, Fedak PWM, Li RK, Dhillon B, Mickle DA. Endothelin Antagonism
and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein. Circulation
2002;105:1890-1896.
9) Verma S, Wang CH, Li SH, Dumont AS, Fedak PWM, Badiwala MV, Dhillon B, Weisel RD, Li RK, Mickle DAG,
Stewart DJ. A Self-Fulfilling Prophecy: C-Reactive Protein Attenuates Nitric Oxide Production and Inhibits
Angiogenesis. Circulation 2002;106:913-919.
10) Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-Reactive Protein
Levels and Impaired Endothelial Vasoreactivity in Patients with Coronary Artery Disease. Circulation
2000;102:1000-1006.
11) Fichtlscherer S, Zeiher AM. Endothelial Dysfunction in Acute Coronary Syndromes: Association with Elevated
C-Reactive Protein Levels. Ann Med 2000;32:515-518.
12) Cleland SJ, Sattar N, Petrie JR, Forouhi NG, Elliott HL, Connell JMC. Endothelial Dysfunction as a Possible
Link Between C-Reactive Protein Levels and Cardiovascular Disease. Clinical Science 2000;98:531-535.
References