Published Online
on July 24, 2006

A more recent version of this article appeared on August 1, 2006

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Submitted on July 25, 2005
Revised on May 5, 2006
Accepted on May 26, 2006

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, and 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.).

^* To whom correspondence should be addressed. E-mail: pamaffia{at}unina.it.

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/ 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.

Key words: angioplasty • balloon • carotid arteries • interleukins

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