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Journal of Lipid Research, Vol. 48, 952-960, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Patient-Oriented Research

Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects

Radjesh J. Bisoendial^*, John J. P. Kastelein^*, Stephan L. M. Peters, Johannes H. M. Levels^*, Rakesh Birjmohun^*, Joris I. Rotmans^*, Daniel Hartman, Joost C. M. Meijers^*, Marcel Levi^* and Erik S. G. Stroes^1,*

^* Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands
deCODE Genetics, Reykjavik, Iceland

Published, JLR Papers in Press, January 26, 2007.

¹ To whom correspondence should be addressed. e-mail: e.s.stroes{at}amc.uva.nl

ABSTRACT

C-reactive protein (CRP) has been suggested to exert direct adverse effects on the vasculature in experimental setups, including endothelial dysfunction and proinflammatory changes. Here, we assessed the consequences of 1.25 mg/kg highly purified recombinant human CRP, administered as an intravenous bolus, in six patients with familial hypercholesterolemia (FH) and six normocholesterolemic subjects. Endothelium-dependent and -independent vasoreactivity to serotonin and nitroprusside, respectively, were assessed using venous occlusion plethysmography before and after CRP infusion. For biochemical analyses, blood was drawn at different time points. At baseline, FH patients showed blunted endothelium-dependent vasodilation (maximum, 89.2 ± 30.0% vs. 117.7 ± 13.1% in normolipidemic subjects; P = 0.037). Procoagulant activity was also higher in FH patients, illustrated by increased prothrombin fragment 1+2 (F₁₊₂) levels (P = 0.030) and plasminogen activator inhibitor type-1 (PAI-1) activity (P = 0.016). Upon CRP challenge, endothelium-dependent vasodilator capacity further deteriorated in FH patients (P = 0.029), whereas no change in vascular reactivity was observed in normolipidemic subjects. Additionally, coagulation activation was augmented in FH patients compared with normolipidemic subjects (P = 0.009 for F₁₊₂ levels; P = 0.018 and P = 0.003 for PAI-1 antigen and activity, respectively). No difference in inflammatory responses was observed between groups. In hypercholesterolemic patients, CRP aggravates endothelial dysfunction and also evokes augmented procoagulant responses. These findings suggest that particularly in hypercholesterolemia, CRP-lowering strategies should be considered in addition to LDL reduction.

Supplementary key words inflammation • atherothrombosis • C-reactive protein

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