Abstract：
γ-bungarotoxin (γ-BGT) is an RGD motif-containing protein, derived from the venom of Bungarus multicinctus, leading to acute death in mice. These RGD motif-containing proteins from snake venom belonging to the disintegrin family can interfere with vascular endothelial homeostasis by directly binding cell surface integrins. Targeting integrins that generate vascular endothelial dysfunction may contribute to γ-BGT poisoning, however, the underlying mechanisms have not been investigated in detail. In this study, the results showed that γ-BGT played a role in -promoting the permeability of the vascular endothelial barrier. Depending on its selective binding to integrin α5 in vascular endothelium (VE), γ-BGT initiated downstream events, including focal adhesion kinase dephosphorylation and cytoskeleton remodeling, resulting in the intercellular junction interruption. Those alternations facilitated paracellular permeability of VE and barrier dysfunction. Proteomics profiling identified that as a downstream effector of the integrin α5 / FAK signaling pathway cyclin D1 partially mediated the cellular structural changes and barrier dysfunction. Furthermore, VE-released plasminogen activator urokinase and platelet-derived growth factor D could serve as potential diagnostic biomarkers for γ-BGT-induced vascular endothelial dysfunction. Our results indicate the mechanisms through which γ-BGT as a novel disintegrin directly interacts with the VE, with consequences for barrier dysfunction.
摘要：
γ-银环蛇毒素（γ-BGT）是一种含RGD基序的蛋白质，来自Bungarusmulticinctus的毒液，导致小鼠急性死亡。这些来自蛇毒的含RGD基序的蛋白质属于解整合素家族，可以通过直接结合细胞表面整合素来干扰血管内皮稳态。靶向产生血管内皮功能障碍的整合素可能有助于γ-BGT中毒，然而,潜在的机制尚未详细研究。在这项研究中,结果表明，γ-BGT对血管内皮屏障的通透性有促进作用。根据其与血管内皮（VE）中整合素α5的选择性结合，γ-BGT启动下游事件，包括粘着斑激酶去磷酸化和细胞骨架重塑，导致细胞间连接中断。这些变化促进了VE的细胞旁通透性和屏障功能障碍。蛋白质组学分析确定，作为整合素α5/FAK信号通路的下游效应物，细胞周期蛋白D1部分介导了细胞结构变化和屏障功能障碍。此外，VE释放的纤溶酶原激活物尿激酶和血小板源性生长因子D可作为γ-BGT诱导的血管内皮功能障碍的潜在诊断生物标志物。我们的结果表明γ-BGT作为一种新型的崩解素直接与VE相互作用的机制，有屏障功能障碍的后果。
