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Histidine‐rich glycoprotein ameliorates endothelial barrier dysfunction through regulation of NF‐κB and MAPK signal pathway
Author(s) -
Gao Shangze,
Wake Hidenori,
Gao Yuan,
Wang Dengli,
Mori Shuji,
Liu Keyue,
Teshigawara Kiyoshi,
Takahashi Hideo,
Nishibori Masahiro
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14711
Subject(s) - microbiology and biotechnology , endothelial stem cell , barrier function , tumor necrosis factor alpha , endothelium , vascular permeability , actin cytoskeleton , rhoa , cytokine , biology , cytoskeleton , signal transduction , chemistry , immunology , in vitro , biochemistry , cell , endocrinology
Background and Purpose Microvascular barrier breakdown is a hallmark of sepsis that is associated with sepsis‐induced multiorgan failure. Histidine‐rich glycoprotein (HRG) is a 75‐kDa plasma protein that was demonstrated to improve the survival of septic mice through regulation of cell shape, spontaneous ROS production in neutrophils, and adhesion of neutrophils to vascular endothelial cells. We investigated HRG's role in the LPS/TNF‐α‐induced barrier dysfunction of endothelial cells in vitro and in vivo and the possible mechanism, to clarify the definitive roles of HRG in sepsis. Experimental Approach EA.hy 926 endothelial cells were pretreated with HRG or human serum albumin before stimulation with LPS/TNF‐α. A variety of biochemical assays were applied to explore the underlying molecular mechanisms on how HRG protected the barrier function of vascular endothelium. Key Results Immunostaining results showed that HRG maintains the endothelial monolayer integrity by inhibiting cytoskeleton reorganization, losses of VE‐cadherin and β‐catenin, focal adhesion kinase degradation, and cell detachment induced by LPS/TNF‐α. HRG also inhibited the cytokine secretion from endothelial cells induced by LPS/TNF‐α, which was associated with reduced NF‐κB activation. Moreover, HRG effectively prevented the LPS/TNF‐α‐induced increase in capillary permeability in vitro and in vivo. Finally, Western blot results demonstrated that HRG prevented the phosphorylation of MAPK family and RhoA activation, which are involved mainly in the regulation of cytoskeleton reorganization and barrier permeability. Conclusions and Implications Taken together, our results demonstrate that HRG has protective effects on vascular barrier function in vitro and in vivo, which may be due to the inhibition of MAPK family and Rho activation.