Abstract 9021: Long Term Stabilization of Expanding Aortic Aneurysms by a Short Course of Cyclosporine A Administration. A Pharmacological Reprogrammation of Cellular Defects in Diseased Aorta.
Once they have formed, abdominal aortic aneurysms (AAAs) tend to expand inexorably as a consequence of aortic destruction/reconstruction unbalance and smooth muscle cell (VSMC) depletion. Pharmacological approaches have consisted so far in permanent drug administration to block tissue destruction. Cyclosporine A (CsA), a member of the calcineurin inhibitor family, induces Transforming Growth Factor-beta 1 (TGF-beta1) and promotes tissue accumulation including in the vasculature, a structural aim to compensate for AAA wall atrophy. We tested the hypothesis that a short course of CsA administration could trigger aortic reconstruction and durably stabilize AAAs, beyond drug interruption.
Methods and results: CsA induced TGF-beta1 and decreased matrix metalloprotease-9 expression dose-dependently in fragments of human AAAs in vitro, and in two animal models of AAA in vivo. CsA prevented AAA formation in the calcium chloride mouse model (14 day diameters: CsA: 0.72+/−0.06 mm; vehicle: 1.10+/−0.05 mm, P=0.008), decreased inflammation and preserved wall elastin and VSMCs. A seven day administration of CsA prevented further expansion of already formed AAAs in a xenograft model in rats, up to seven weeks after drug withdrawal (diameter increase: CsA: 11.8+/−6.0 %; vehicle: 45.2+/−6.1%, P=0.017), down-regulated wall inflammation, and increased alpha-SMA positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, alpha-SMA positive cell accumulation and diameter stabilization in expanding AAAs, demonstrating that the pleïotropic activity of TGF-beta is required for CsA to restore the capability of the diseased aneurysm wall to withstand arterial pressure without dilating further.
Conclusion: Pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the destructive/reconstructive balance towards healing. We provide a model of pharmacological induction of a cytokine and aortic wall cellular repair as an alternative to gene or cell therapy. Short duration of CsA administration may obviate systemic side effects and allow for a local, high dose delivery from an endovascular plate-form.
- © 2010 by American Heart Association, Inc.