A critical role for Lyn kinase in strengthening endothelial integrity and barrier function
A critical role for Lyn kinase in strengthening endothelial integrity and barrier function
复制标题
DOI：
10.1182/blood-2013-03-491423
复制
发表时间：
2013-12-12
期刊：
影响因子：
20.3
通讯作者：
Li, Zhenyu
中科院分区：
文献类型：
--
作者：
Han, Jingyan;Zhang, Guoying;Li, Zhenyu
Src家族激酶(Sfk)、c-src和Yes在包括脂多糖(LPS)和血管内皮生长因子(VEGF)在内的各种刺激下介导血管渗漏。在这里，我们定义了另一种SFK的相反功能，LYN，与其他SFK相反，它加强内皮连接，从而抑制血管通透性的增加。与野生型小鼠相比，缺乏LYN的小鼠在脂多糖诱导的内毒素血症中表现出更高的死亡率，并且对脂多糖或血管内皮生长因子攻击的反应增加了血管通透性。与野生型小鼠相比，野生型LYN基因敲除小鼠具有更高的血管通透性，提示内皮LYN在维持血管屏障中发挥作用。小干扰RNA介导的Lyn下调破坏了内皮屏障的完整性，而Lyn的结构性活性突变体的表达增强了该屏障。然而，下调Lyn并不影响内毒素诱导的内皮通透性。我们证明LYN与粘着斑激酶(FAK)的结合以及FAK在酪氨酸残基576/577和925位的磷酸化对于LYN依赖的内皮粘附素连接的稳定是必需的。因此，与c-Src和Yes不同，c-Src和Yes增加了血管对刺激的通透性，而Lyn通过FAK的磷酸化来稳定内皮连接。因此，激活Lyn激酶的治疗药物可能会加强内皮屏障连接，从而具有抗炎作用。
The Src family kinases (SFKs) c-Src and Yes mediate vascular leakage in response to various stimuli including lipopolysaccharide (LPS) and vascular endothelial growth factor (VEGF). Here, we define an opposing function of another SFK, Lyn, which in contrast to other SFKs, strengthens endothelial junctions and thereby restrains the increase in vascular permeability. Mice lacking Lyn displayed increased mortality in LPS-induced endotoxemia and increased vascular permeability in response to LPS or VEGF challenge compared with wild-type littermates. Lyn knockout mice repopulated with wild-type bone marrow-derived cells have higher vascular permeability than wild-type mice, suggesting a role of endothelial Lyn in the maintenance of the vascular barrier. Small interfering RNA-mediated down-regulation of Lyn disrupted endothelial barrier integrity, whereas expression of a constitutively active mutant of Lyn enhanced the barrier. However, down-regulation of Lyn did not affect LPS-induced endothelial permeability. We demonstrate that Lyn association with focal adhesion kinase (FAK) and phosphorylation of FAK at tyrosine residues 576/577 and 925 were required for Lyn-dependent stabilization of endothelial adherens junctions. Thus, in contrast to c-Src and Yes, which increase vascular permeability in response to stimuli, Lyn stabilizes endothelial junctions through phosphorylation of FAK. Therefore, therapeutics activating Lyn kinase may strengthen the endothelial barrier junction and hence have anti-inflammatory potential.