IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome.

ABSTRACT

Although considerable evidence implicates the cytokine interlukin-18 (IL-18) in metabolic syndrome (MetS), the direct effect of IL-18 on vascular changes of MetS remains unknown. We investigated the chronic in vivo effect of IL-18 on development of MetS and vascular inflammation and remodeling by overexpressing IL-18 protein in fructose-fed rats (FFR), a model of MetS using intravenous administration of an adenovirus encoding rat IL-18. Increased serum IL-18 and vascular inflammatory response were found in FFR. Overexpression of IL-18 aggravated insulin resistance and enhance vascular inflammation and remodeling, which can be reflected by increased aortic expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and enhanced infiltration of macrophages and increased aortic wall thickness and wall-to-lumen ratio. Interestingly, the levels of interleukin-1 receptor-associated kinase 1 (IRAK1) and the activity of nucleus factor-kappaB (NF-kappaB) were also significantly increased. Together, these results indicated that chronic elevated IL-18 levels at a supraphsiological concentration aggravated insulin resistance, enhanced vascular inflammation and remodeling, probably by increasing the level of IRAK1 and the activity of NF-kappaB. Targeting expression of IL-18 or its specific downstream mediators may retard the progression of MetS and its complications.