HMGB1‐induced vascular hyperpermeability requires β‐catenin phosphorylation

Abstract

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 Y654 and Y142 ameliorated 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 for β‐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.Support or Funding InformationThis work was supported by National Natural Science Foundation of China (81670076, 31871183); Guangdong Natural Science Foundation (2017A030313462); General Program from Natural Science Foundation of China (81370226, 81170297); The Team project of Natural Science Foundation of Guangdong, China (S2013030013217); Grant of NSFC Guangdong Joint Foundation of China (U1601225); Key Scientific and Technological Program of Guangzhou City (201607020016); Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation [pdjh2017a0095].