Role of Girdin in intimal hyperplasia in vein grafts and efficacy of atelocollagen-mediated application of small interfering RNA for vein graft failure

ObjectiveIntimal hyperplasia is a major obstacle to patency in grafted veins. Although migration and proliferation of vascular smooth muscle cells (SMCs) pivotally affect the vascular remodeling process, no therapy has been established to prevent intimal hyperplasia of vein grafts. We previously reported that the actin-binding protein Girdin crucially affects arterial remodeling. In this study, we investigated the role of Girdin in venous SMCs and evaluated a therapeutic strategy for vein graft failure in vivo using small interfering RNA (siRNA) that targets Girdin.MethodsWe investigated the relationship between Girdin expression and intimal hyperplasia using a rabbit vein graft model. Vein grafts under low-flow conditions were performed in Japanese White rabbits. For in vitro analyses, we isolated primary venous SMCs from vein graft neointima. siRNA that targets Girdin was mixed with atelocollagen, which stabilizes and releases nucleic acid reagents slowly and is applied perivascularly to the vein grafts at operation. Intimal hyperplasia was evaluated 4 weeks later.ResultsIn the rabbit model, increased Girdin expression was seen in the neointima after the grafting operation. Using primary venous SMCs, we showed that Girdin is required for rearrangement of the actin cytoskeleton in venous SMCs and that siRNA-mediated Girdin knockdown significantly reduced venous SMC migration and proliferation. Girdin knockdown via perivascular application of siRNA using atelocollagen markedly reduced intimal thickening after the grafting operation.ConclusionsDepletion of Girdin attenuated venous SMCs migration and proliferation in vitro and intimal hyperplasia in vein grafts in vivo. Our findings suggest that Girdin affects migration and proliferation of vascular SMCs in vein grafts and that controlled release of Girdin siRNA using atelocollagen could be a novel therapeutic strategy for vein graft failure.

Clinical RelevanceIntimal hyperplasia is a major obstacle to patency after vein grafting. Although migration and proliferation of vascular smooth muscle cells pivotally affect the vascular remodeling process, no therapy has been established to prevent intimal hyperplasia of vein grafts. Here, we report that depletion of the actin-binding protein Girdin attenuated migration and proliferation of venous smooth muscle cells in vitro and intimal hyperplasia in vein grafts in vivo. Our findings indicate that perivascular application of Girdin small interfering RNA using atelocollagen could be a novel therapeutic strategy for vein graft failure.