A021 Prevention and stabilization of experimental aortic abdominal aneurysms by cyclosporine

Background Cyclosporine, an effective immunosuppressive, induces long-term abnormal extracellular matrix deposition and decreases MMP-dependent proteolysis through TGF-beta induction. Overexpression of TGF-beta has been shown to promote wall reconstruction and stabilization of experimental abdominal aortic aneurysms (AAA). We thus evaluated the ability of cyclosporine, possibly through TGF-beta to prevent and stop AAA expansion. Methods and Results The effect of cyclosporine on AAA remodeling, TGF-beta and matrix metalloprotease (MMP)-9 expression was evaluated on human AAA explants and in two experimental models of AAA: the periaortic CaCl2 and the xenograft models in mice and rats, respectively. Incubation of human AAA explants during 24h with cyclosporine (1 or 2 μg/ml) induced an increase in TGF-beta and a decrease in MMP-9 release in conditioned media. A preventive treatment with cyclosporine (50 mg/kg/day, i.p., starting 2 days before AAA generation and maintained for 2 weeks) in CaCl2 model in mice was associated with prevention of AAA development (external diameter: 0.72±0.06 vs 1.10±0.05 mm in cyclosporine- and vehicle-treated mice, respectively, p=0.008), preservation of medial elastin and smooth muscle cell content and an increase in TGF-beta and a decrease in MMP-9 aortic content. Furthermore, short-term cyclosporine treatment (5 mg/kg/day, s.c., for 7 days starting 2 weeks after xenograft) was sufficient to promote long-term (10 weeks after xenograft) healing and stabilization of already-formed AAA in the rat xenograft model (aortic diameter increase: 11.8±6.0 and 45.2±6.1 % in cyclosporine- and vehicle-treated rats, respectively, p=0.017). This curative effect was accompanied by a decreased infiltration of monocyte/macrophages and T lymphocytes, an induction of aortic TGF-beta and tissue metalloprotease inhibitor-1 and a decrease in aortic MMP-9 mRNA levels. Conclusions Cyclosporine induced TGF-beta and inhibited MMP-9 release from human AAA explants. Cyclosporine not only prevented the development of AAA but also stop AAA enlargement in experimental AAA models. These protective effects were associated with increased aortic TGF-beta signaling. We further demonstrated that a short induction treatment with cyclosporine is sufficient to promote long-term AAA stabilization in rats and should thus be considered for treatment of human AAA.