Abstract 13817: Macrophage-Derived Il-18 Evokes a Pro-Inflammatory Positive-Feedback Loop During the Remodeling of the Aging Vasculature
Objective: Aging exaggerates neointimal hyperplasia. This study reveals a mechanism by which aging sustains leukocyte adhesion, vascular inflammation and neointima formation.
Methods and Results: The effect of aging on vascular remodeling was assessed in the rat balloon injury model using time-course microarray analysis, immunohistochemistry, and LINCOplex immunoassays. As we previously described, the injured arteries in aging rats (22 month-old) developed thicker neointimas than those in their younger counter parts (4 month-old) (I/M: 0.8 ± 0.2 vs. 0.54 ± 0.15, p=0.008). Microarray analysis revealed an early up-regulation of fibrinogen b and γ genes in aging rats which led to an exaggerated focal accumulation of fibrinogen in the injured vascular wall. The accumulation of fibrinogen increased post-injury leukocyte adhesion and extravasation and therefore, exacerbated vascular inflammation. In fact, neointimal hyperplasia in aging rats was associated with an elevated number of tissue macrophages (aging vs. young: 3200 ± 44 vs. 700 ±13, CD68+ cells per mm2) and an exaggerated accumulation of vascular IL-18. This pro-inflammatory cytokine was 23-fold more abundant in the injured vasculature of aging animals than in that of young rats. Importantly, macrophage depletion by clodronate liposomes suppressed aging-related neointimal hyperplasia and accumulation of IL-18. The role of IL-18 in establishing a pro-inflammatory positive-feedback loop during neointimal hyperplasia was further demonstrated using in vitro culture and adhesion assays. It was found that incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen. Interestingly, IL-18 also inhibited vascular smooth muscle apoptosis, thus favoring the formation of neointima. The addition of IL-18 to camptothesin-treated cultures significantly decreased the number of AnexinV- PI positive cells with respect to those cultures where no cytokine was added.
Conclusion: Our data underscore the pivotal role of three pro-inflammatory elements, namely, fibrinogen, macrophages, and IL-18, in the establishment of a positive feedback mechanism that could play a prominent role in chronic inflammation and post-injury neointimal formation.
- © 2011 by American Heart Association, Inc.