This document summarizes several studies on C-reactive protein (CRP) and its role in atherosclerosis. It finds that CRP is an active player in atherosclerosis rather than just a risk marker. CRP was found to directly promote endothelial cell adhesion molecule expression, macrophage LDL uptake, and monocyte chemoattractant protein-1 secretion. Blocking CRP's effects through endothelin receptor antagonism or interleukin-6 inhibition reduced these proatherogenic effects. Therefore, CRP may directly facilitate the inflammatory process in atherosclerosis and represent a potential therapeutic target for reducing cardiovascular risk.

1. Editorial Slides
VP Watch, April 24, 2002, Volume 2, Issue 16
CRP; A Risk Factor Not a Risk Marker?

2. •
• CRP is an acute-phase reactant that serves as a
pattern-recognition molecule in the innate immune
system.
• Ridker et al analyzed data from the Physician’s Health
Study and demonstrated that circulating CRP levels
provided significant incremental prognostic information
over and above total cholesterol to HDL ratio. 4
• CRP levels have been considered to reflect the extent of
inflammatory reactions in the atherosclerotic vessels.
5,6
• Also measures of body fat are strongly associated with
circulating levels of CRP and fibrinogen. 7

3.  High-sensitivity CRP (HSCRP) is a strong independent predictor of
endothelial dysfunction, future myocardial dysfunction, stroke, peripheral
artery disease, and vascular death among individuals without known
cardiovascular disease. 10,11
 Ridker et al. in cohort of women measured levels of homocysteine,
lipoprotein(a), several inflammatory parameters including HSCRP, and a
full lipid panel as markers of subsequent vascular risk. 12
 They showed that HSCRP was the single strongest predictor of risk. In
multivariate analysis, only HSCRP level and total / HDL ratio proved to
have independent predictive value once age, smoking status, obesity,
hypertension, family history, and diabetes also were accounted for.

4.  Yeh and colleagues found that CRP can induce
adhesion molecule expression by human endothelial
cells. 3
 They showed that CRP, at concentrations 5 µg/mL,
has significant pro-inflammatory effects in both umbilical
vein and coronary artery endothelial cells, inducing high
levels of expression of ICAM-1, VCAM-1, and
E-selectin. 3

5.  Lemieux and colleagues showed significant
relationships between plasma CRP and measures of
adiposity and of insulin resistance but no association
with the plasma lipoprotein-lipid profile in healthy
asymptomatic men. 8
 Therefore, these results suggest that abdominal
obesity is the critical correlate of elevated CRP
concentrations found in men with atherogenic
dyslipidemia of the insulin resistance syndrome.
 Yudkin et al. have shown that an increased plasma
CRP concentration was related to the features of
insulin resistance syndrome and to endothelial
dysfunction. 9

6.  As reported in this week of VP Watch,
Verma and colleagues showed that incubation
of human venous endothelial cells with
recombinant human CRP resulted in a marked
increase in ICAM-1 and VCAM-1 expression.
 They found that incubation of human
endothelial cells with recombinant CRP resulted
in a marked increase in ICAM-1 and VCAM-1
expression and also increasing monocyte
chemoattractant chemokine-1 production.13

7. CRP Induces ET-1 and IL-6 Production
CRP
0
50
100
150
200
Control CRP+Bosentan
IL-6
Effects of human recombinant CRP (25
µg/mL, 24 hours) on IL-6 production in human
saphenous vein endothelial cells (2nd
through 5th passage) in the presence and
absence of bosentan (10 µmol/L).
0.0
2.0
4.0
6.0
8.0
10.0
12.0
Control CRP CRP+IL-
6Ab
ET-1
Effects of human recombinant CRP (25
µg/mL, 24 hours) on ET-1 production in
human saphenous vein endothelial cells (2nd
through 5th passage) in the presence and
absence of anti–IL-6 antibody (5 µmol/L).
Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein; Subodh Verma,
Shu-Hong Li, Mitesh V. Badiwala, Richard D. Weisel, Paul W.M. Fedak, Ren-Ke Li, Bikramjit Dhillon, and Donald A.G. Mickle

8. Effect of Human Recombinant CRP on LDL
Uptake in Human Macrophages
LDL
LDL+CRP
LDL+CRP+Bosentan
LDL+CRP+IL-6Ab
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
LDL LDL+CRP+IL-6Ab
CD14
+CD3
2
Positi
ve
Cells
The effects of CRP on LDL uptake were assessed in macrophages
using immunofluorescent labeling of CD32 and CD14.
Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein; Subodh Verma,
Shu-Hong Li, Mitesh V. Badiwala, Richard D. Weisel, Paul W.M. Fedak, Ren-Ke Li, Bikramjit Dhillon, and Donald A.G. Mickle

9. • Verma and colleagues showed that
both bosentan (endothelin antagonism)
and anti–IL-6 antibodies attenuated
CRP-mediated expression of adhesion
molecules, MCP-1 secretion, and
macrophage LDL uptake. 13

10. Conclusion
 CRP directly facilitates endothelial cell adhesion
molecule expression, MCP-1 production, and
macrophage LDL uptake.
 CRP may not be only a marker rather an active players
in atherosclerosis.
 CRP may be the link between obesity (insulin
resistance) and atherosclerosis.

11. Questions:
• Now that we hear CRP is more than a
marker, the question is whether this role of
CRP specifically pertains to macrophages
in atherosclerosis or CRP plays similar
inflammatory role in other chronic
inflammatory diseases such as
rheumatoid arthritis?

12. Questions:
• If CRP is indeed a risk factor, should we try to
lower CRP? In other words, do we need to
launch CRP lowering trial? (like lipid lowering
trial)
• Can we create an animal model in which
increasing CRP increases plaque inflammation?
• Knowing the independent risk value of CRP,
should it be included in Framingham Risk
Score?

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