Girdin 在静脉移植物内膜增生中的作用及应用小干扰 RNA 经胶原蛋白介导治疗静脉移植物失败的疗效。
Role of Girdin in intimal hyperplasia in vein grafts and efficacy of atelocollagen-mediated application of small interfering RNA for vein graft failure.
机构信息
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
出版信息
J Vasc Surg. 2014 Aug;60(2):479-489.e5. doi: 10.1016/j.jvs.2013.06.080. Epub 2013 Aug 12.
OBJECTIVE
Intimal 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.
METHODS
We 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.
RESULTS
In 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.
CONCLUSIONS
Depletion 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.
目的
内膜增生是移植静脉通畅的主要障碍。虽然血管平滑肌细胞（SMC）的迁移和增殖对血管重塑过程有重要影响，但目前还没有预防静脉移植物内膜增生的治疗方法。我们之前报道过，肌动蛋白结合蛋白 Girdin 对动脉重塑有重要影响。在这项研究中，我们研究了 Girdin 在静脉 SMC 中的作用，并通过靶向 Girdin 的小干扰 RNA（siRNA）在体内评估了一种治疗静脉移植物失败的策略。
方法
我们使用兔静脉移植物模型研究了 Girdin 表达与内膜增生之间的关系。在日本白兔中进行低流量条件下的静脉移植物手术。为了进行体外分析，我们从静脉移植物新生内膜中分离出原代静脉 SMC。靶向 Girdin 的 siRNA 与 ATelocollagen 混合，后者缓慢稳定并释放核酸试剂，并在手术时沿血管周围应用于静脉移植物。4 周后评估内膜增生。
结果
在兔模型中，移植手术后可见 Girdin 在新内膜中的表达增加。使用原代静脉 SMC，我们表明 Girdin 是静脉 SMC 中肌动蛋白细胞骨架重排所必需的，并且 siRNA 介导的 Girdin 敲低显著减少了静脉 SMC 的迁移和增殖。通过 ATelocollagen 沿血管周围应用 siRNA 进行 Girdin 敲低，显著减少了移植手术后的内膜增厚。
结论
Girdin 的耗竭在体外减弱了静脉 SMC 的迁移和增殖，在体内减弱了静脉移植物的内膜增生。我们的发现表明 Girdin 影响静脉移植物中血管 SMC 的迁移和增殖，并且使用 ATelocollagen 控制释放 Girdin siRNA 可能是治疗静脉移植物失败的一种新策略。
Zotero 插件