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(Circulation. 2006;114:430-437.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Neutralization of Interleukin-18 Inhibits Neointimal Formation in a Rat Model of Vascular Injury

Pasquale Maffia, PhD; Gianluca Grassia, PhD; Paola Di Meglio, PhD; Rosa Carnuccio, PhD; Liberato Berrino, MD; Paul Garside, PhD; Angela Ianaro, PhD^*; Armando Ialenti, PhD^*

From the Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy (P.M., G.G., P.D.M., R.C., A.I., A.I.); Division of Immunology, Infection and Inflammation and Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK (P.M.); Excellence Research Center for Cardiovascular Diseases and Department of Experimental Medicine, Second University of Naples, Naples, Italy (L.B.); and Centre for Biophotonics, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, UK (P.G.).

Correspondence to Pasquale Maffia, Department of Experimental Pharmacology, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy. E-mail pamaffia{at}unina.it

Received July 25, 2005; de novo received November 22, 2005; revision received May 5, 2006; accepted May 26, 2006.

Background— Studies in humans and animal models suggest that interleukin-18 (IL-18) plays a crucial role in vascular pathologies. IL-18 is a predictor of cardiovascular death in angina and is involved in atherotic plaque destabilization. Higher IL-18 plasma levels also are associated with restenosis after coronary artery angioplasty performed in patients with acute myocardial infarction. We investigated the effective role of IL-18 in neointimal formation in a balloon-induced rat model of vascular injury.

Methods and Results— Endothelial denudation of the left carotid artery was performed by use of a balloon embolectomy catheter. Increased expression of IL-18 and IL-18R/ß mRNA was detectable in carotid arteries from days 2 to 14 after angioplasty. The active form of IL-18 was highly expressed in injured arteries. Strong immunoreactivity for IL-18 was detected in the medial smooth muscle cells at days 2 and 7 after balloon injury and in proliferating/migrating smooth muscle cells in neointima at day 14. Moreover, serum concentrations of IL-18 were significantly higher among rats subjected to vascular injury. Treatment with neutralizing rabbit anti-rat IL-18 immunoglobulin G significantly reduced neointimal formation (by 27%; P<0.01), reduced the number of proliferating cells, and inhibited interferon-, IL-6, and IL-8 mRNA expression and nuclear factor-B activation in injured arteries. In addition, in vitro data show that IL-18 affects smooth muscle cell proliferation.

Conclusions— These results identify a critical role for IL-18 in neointimal formation in a rat model of vascular injury and suggest a potential role for IL-18 neutralization in the reduction of neointimal development.

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