Role of Interleukin-18 in vascular injury: a new pharmacological target for the prevention of restenosis

Background: Studies in humans as well as in animal models suggest that interleukin-18 (IL-18) plays a crucial role in vascular pathologies. IL-18 is a strong predictor of cardiovascular death in angina and is involved in atherotic plaque destabilization. Higher IL-18 plasma levels are also associated with restenosis after coronary artery angioplasty performed in patients with acute myocardial infarction. We investigated the effective role of IL-18 in neointima formation in a rat model of vascular injury, known as balloon angioplasty. Methods and Results: Endothelial denudation of the left carotid artery was performed by using a balloon embolectomy catheter. Increased expression of IL-18 and IL-18R?/? mRNA was detectable in carotid arteries from day 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 day 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. Rats treatment with neutralizing rabbit anti-rat IL-18 IgG significantly reduced by 27% (P<0.01) neointima formation. In addition, IL-18 neutralization reduced number of proliferating cells, inhibited IFN-?, IL-6, IL-8 mRNA expression and nuclear factor-?B activation in injured arteries. Conclusions: These results identify for the first time a critical role for IL-18 in neointima formation in a rat model of vascular injury and suggest a potential role for IL-18 neutralization in reduction of neointima development and progression.