Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes
Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes
复制标题
DOI：
10.1182/blood-2006-04-008532
复制
发表时间：
2006-10-15
期刊：
影响因子：
20.3
通讯作者：
Baker, Andrew H.
中科院分区：
文献类型：
--
作者：
Parker, Alan L.;Waddington, Simon N.;Baker, Andrew H.
局部递送后，腺病毒 (Ad) 血清型 5 病毒使用柯萨奇和 Ad 受体 (CAR) 进行细胞结合，并使用 α(v) 整合素进行内化。然而，当全身给药时，它们在肝脏向性中的作用受到限制，因为 CAR 允许的病毒和突变的病毒表现出相似的生物分布，最近的这一发现归因于凝血因子 (F) IX 或补体蛋白 C4BP 与腺病毒纤维结合，并“桥接”低密度脂蛋白受体相关蛋白或硫酸乙酰肝素蛋白聚糖。在这里，我们表明，除了 FIX 之外，维生素 K 依赖性因子 FX、蛋白 C 和 FVII 也可以增强体外肝细胞转导，但凝血酶原 (FII)、FXI 和 FXII 则不能。这种现象不依赖于蛋白水解激活或细胞信号传导活性，并且 FX 是由直接病毒因子结合介导的。在离体肝脏灌注模型中，Human FX 显着增强了 CAR 许可病毒和突变病毒的肝细胞转导。在体内，华法林对维生素 K 依赖性酶原的整体下调显着减少了肝脏对 CAR 删除的 Ads 的摄取；然而，这种现象被人类外汇的急性输注完全挽救了。我们的结果表明，不同的维生素 K 依赖性凝血因子在体外和体内介导腺病毒肝细胞转导中具有共同且关键的作用。
Upon local delivery, adenovirus (Ad) serotype 5 viruses use the coxsackie and Ad receptor (CAR) for cell binding and alpha(v) integrins for internalization. When administered systemically, however, their role in liver tropism is limited because CAR-permissive and mutated viruses show similar biodistribution, a finding recently attributed to blood coagulation factor (F) IX or complement protein C4BP binding to the adenovirus fiber and "bridging" to either low-density lipoprotein receptor-related protein or heparan sulfate proteoglycans. Here, we show that hepatocyte transduction in vitro can be enhanced by the vitamin K-dependent factors FX, protein C, and FVII in addition to FIX but not by prothrombin (FII), FXI, and FXII. This phenomenon was not dependent on proteolytic activation or cell signaling activity and for FX was mediated by direct virus-factor binding. Human FX substantially enhanced hepatocyte transduction by CAR-permissive and mutated viruses in an ex vivo liver perfusion model. In vivo, global down-regulation of vitamin K-dependent zymogens by warfarin significantly diminished liver uptake of CAR-deleted Ads; however, this phenomenon was fully rescued by acute infusion of human FX. Our results indicate a common and pivotal role for distinct vitamin K-dependent coagulation factors in mediating hepatocyte transduction by adenoviruses in vitro and in vivo.