Editorial Slides VP Watch, April 24, 2002, Volume 2, Issue 16

CRP; A Risk Factor Not a Risk Marker?

• • 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

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.

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

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

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

CRP Induces ET-1 and IL-6 Production

CRP

0

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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).

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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

Effect of Human Recombinant CRP on LDL Uptake in Human Macrophages

LDL

LDL+

CR

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LDL+

CR

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osen

tan

LDL+

CR

P+I

L-6A

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10.0

20.0

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LDL LDL+CRP+IL-6Ab

CD14+CD32PositiveCells

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

• 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

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.

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?

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?

1) Libby P, Geng YJ, Sukhova GK, et al. Molecular determinants of atherosclerotic plaque vulnerability. Ann N Y Acad Sci. 1997;811:134–145.

2) Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation. 1999;100:2124–2126

3) Pasceri, V., Willerson, J. T., Yeh, E. T. H. (2000). Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells. Circulation 102: 2165-2168

4) Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. 1998;97:2007–2011

5) Heinrich J, Schulte H, Schönfeld R, Köhler E, Assmann G. Association of variables of coagulation, fibrinolysis and acute-phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the brain. Thromb Haemost. 1995;73:374–378

6) Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentrations of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97:425–428

7) Festa A, D'Agostino R Jr, Williams K, Karter AJ, Mayer-Davis EJ, Tracy RP, Haffner SM.The relation of body fat mass and distribution to markers of chronic inflammation.Int J Obes Relat Metab Disord. 2001 Oct;25(10):1407-15

8) Lemieux I, Pascot A, Prud'homme D, Almeras N, Bogaty P, Nadeau A, Bergeron J, Despres JP.Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity.Arterioscler Thromb Vasc Biol. 2001 Jun;21(6):961-7

9) Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol. 1999;19:972–978

10) Ridker PM. Novel risk factors and markers for coronary disease. Adv Intern Med. 2000; 45: 391–41811) Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated high-sensitivity C-reactive protein assay. Clin

Chem. 1999; 45: 2136–214112) Ridker PM, Hennekens CH, Buring JE, et al. C reactive protein and other markers of inflammation in the

prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–84313) 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

References