Published online before print October 7, 2004, doi: 10.1161/01.ATV.0000147126.99529.0a
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Overexpression of IL-18 Decreases Intimal Collagen Content and Promotes a Vulnerable Plaque Phenotype in Apolipoprotein-E–Deficient Mice
From the Division of Biopharmaceutics (R.d.N., J.H.v.d.T., C.J.N.V., J.K., Th.J.C.v.B., E.A.L.B.) and the Department of Cardiology (R.d.N., J.W.J., E.E.v.d.W.), Leiden University Medical Center, Leiden, the Netherlands.
Correspondence to R. de Nooijer, LACDR, Division of Biopharmaceutics, Gorlaeus Laboratory, PO Box 9502, 2300 RA Leiden, the Netherlands. E-mail r.de.nooijer{at}chem.leidenuniv.nl
Objective— Although IL-18 has been implicated in atherosclerotic lesion development, little is known about its role in advanced atherosclerotic plaques. This study aims to assess the effect of IL-18 overexpression on the stability of preexisting plaques.
Methods and Results— Atherosclerotic lesions were elicited in carotid arteries of apolipoprotein E (apoE)-deficient mice (n=32) by placement of a perivascular collar. Overexpression of IL-18 was effected by intravenous injection of an adenoviral vector 5 weeks after surgery. Two weeks after transduction, lesions were analyzed histologically with regard to plaque morphology and composition or by real-time polymerase chain reaction. No difference in plaque size was detected between groups. In the Ad.IL-18–treated group, 62% of lesions displayed a vulnerable morphology or even intraplaque hemorrhage as compared with only 24% in the controls (P=0.037). In agreement, IL-18 overexpression reduced intimal collagen by 44% (P<0.003) and cap-to-core ratio by 41% (P<0.002). Although IL-18 did not affect the expression of collagen synthesis-related genes, it was found to enhance the collagenolytic activity of vascular smooth muscle cells in vitro, suggesting that the low collagen content is attributable to matrix degradation rather than to decreased synthesis.
Conclusion— Systemic IL-18 overexpression markedly decreases intimal collagen content and cap thickness, leading to a vulnerable plaque morphology.
The effect of IL-18 overexpression on the stability of preexisting advanced atherosclerotic lesions was studied in apoE-deficient mice. A marked decrease in intimal collagen content and an increase in the incidence of vulnerable plaque morphology were observed. It is suggested that IL-18 increases extracellular matrix degradation.
Key Words: atherosclerosis • vulnerable plaque • adenovirus • IL-18 • collagen
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