Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China.
Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China.
J Mol Cell Cardiol. 2019 Feb;127:174-184. doi: 10.1016/j.yjmcc.2018.12.012. Epub 2018 Dec 25.
Endothelial hyperpermeability is a hallmark of acute lung injury in response to sepsis. The imbalance between adherence junction (AJ) mediated cell-cell adherence forces and stress fiber driven contractile forces contributes to increased endothelial permeability. Here, we spotlight the effects of β-catenin Y654 andY142 phosphorylation on HMGB1-mediated endothelial barrier leakage.
Our results showed that phospho-deficiencies at both β-catenin Y654and Y142ameliorated pulmonary vascular dysfunction in male C57 mice receiving a cecal ligation and puncture operation. In vitro analysis indicated that high mobility group box-1 protein (HMGB1) triggered β-catenin Y654 and Y142 phosphorylation, causing β-catenin translocation and adherence junction (AJ) disruptions as well as cytoskeleton rearrangement. In addition,β-catenin Y654 dephosphorylation attenuated HMGB1-mediated dissociation of VE-cadherin/β-catenin and, hence, partially prevented endothelial hyperpermeability. β-catenin Y142 dephosphorylation abolished HMGB1-induced uncoupling of β-catenin and α-catenin, suppressed cytoskeletal reassembly and, hence, alleviated endothelial hyperpermeability. Further investigation demonstrated that RAGE and Src were required forβ-catenin Y654 phosphorylation in response to HMGB1, while FAK was responsible for HMGB1-triggered β-catenin Y142 phosphorylation.
In sum, this study revealed the role of β-catenin Y654 and Y142 phosphorylation in HMGB1-mediated endothelial hyperpermeability through dysregulation between adherence and contractile forces. This result advances understanding of the mechanisms underlying pulmonary vascular hyperpermeability in sepsis.
内皮细胞通透性增加是脓毒症导致急性肺损伤的一个标志。黏附连接（AJ）介导的细胞-细胞黏附力与应力纤维驱动的收缩力之间的失衡导致内皮通透性增加。在这里，我们重点研究β-连环蛋白 Y654 和 Y142 磷酸化对高迁移率族蛋白 B1（HMGB1）介导的内皮屏障渗漏的影响。
我们的结果表明，在接受盲肠结扎和穿刺手术的雄性 C57 小鼠中，β-连环蛋白 Y654 和 Y142 的磷酸缺陷均改善了肺血管功能障碍。体外分析表明，高迁移率族蛋白 B1（HMGB1）触发β-连环蛋白 Y654 和 Y142 磷酸化，导致β-连环蛋白易位和黏附连接（AJ）破坏以及细胞骨架重排。此外，β-连环蛋白 Y654 去磷酸化减弱了 HMGB1 介导的 VE-钙黏蛋白/β-连环蛋白解离，从而部分防止了内皮通透性增加。β-连环蛋白 Y142 去磷酸化消除了 HMGB1 诱导的β-连环蛋白和α-连环蛋白解偶联，抑制了细胞骨架重排，从而缓解了内皮通透性增加。进一步的研究表明，RAGE 和 Src 是 HMGB1 反应中β-连环蛋白 Y654 磷酸化所必需的，而 FAK 则负责 HMGB1 触发的β-连环蛋白 Y142 磷酸化。
总之，这项研究揭示了β-连环蛋白 Y654 和 Y142 磷酸化在 HMGB1 介导的内皮通透性增加中的作用，通过黏附力和收缩力之间的失调。这一结果提高了对脓毒症中肺血管通透性增加机制的理解。
