Abstract 12978: Atelocollagen-Delivered Small Interfering RNA Targeting Girdin Attenuates Intimal Hyperplasia in Vein Grafts in vivo
Background: Intimal hyperplasia is a major obstacle to patency after vein grafting. Although it is well established that the migration and proliferation of vascular smooth muscle cells (VSMCs) have pivotal roles in the vascular remodeling process, there is no established therapy to prevent intimal hyperplasia of vein grafts. We have reported that Akt substrate Girdin is involved in the migration and proliferation of arterial VSMCs. However, little information is available about the function of Girdin in venous VSMCs and their rolls in vein grafts. In this study, we investigated the role of Girdin in migration and proliferation of venous VSMCs in vitro and intimal hyperplasia in vein grafts in vivo, and assessed the hypothesis that small interfering RNA (siRNA) targeting Girdin is a new therapeutic candidate.
Methods and Results: Experiments were performed with primary VSMCs isolated from neointima of rabbit vein grafts in vitro, and rabbit vein graft model in vivo. siRNA -mediated knockdown of Girdin significantly reduced venous VSMCs migration measured by wound-healing assay (width 712 ± 51 μ m vs. 510 ± 50 μ m, P < 0.01, n=3) and proliferation measured by WST-1 (P < 0.01, n = 5). In vivo, Girdin localizes in VSMCs in the media and the neointima, and the expression level of Girdin reached a peak 14 days after grafting operation. Knockdown of the gradually increasing expression of Girdin was achieved by perivascular application of siRNA using atelocollagen. The intimal thickness and the intima-media ratio at 28 days after grafting operation were both reduced by this treatment compared with controls (intima : 0.09 ± 0.01 vs. 0.22 ± 0.05 mm, p < 0.01. intima-media ratio : 0.67 ± 0.08 vs. 1.76 ± 0.24 mm, P < 0.01., n = 5).
Conclusions: Depletion of Girdin attenuated venous VSMCs migration and proliferation in vitro and intimal hyperplasia in vein grafts in vivo. These results support that the combination of siRNA and its controlled release could be a new therapeutic strategy for vein graft failure and that Girdin is a potent molecular target for prevention of intimal hyperplasia in vein grafts.
- © 2012 by American Heart Association, Inc.