Unfractionated Heparin Alleviates Human Lung Endothelial Barrier Dysfunction Induced by High Mobility Group Box 1 Through Regulation of P38-GSK3ß-Snail Signaling Pathway.
Cell Physiol Biochem
; 46(5): 1907-1918, 2018.
Article
em En
| MEDLINE
| ID: mdl-29719300
ABSTRACT
BACKGROUND/AIMS:
The high mobility group box 1 (HMGB1) has been regarded as an important inflammatory mediator. Previous studies showed the involvement of HMGB1 protein in the dysfunction of endothelial barrier function during acute lung injury. However, the molecular mechanism remains unclear.METHODS:
In this study, we used recombinant human HMGB1 (rhHMGB1) and HMGB1 plasmid to treat human pulmonary microvascular endothelial cell (HPMECs). We examined endothelial permeability by measuring TEER value and HRP flux. Western blot and real-time PCR were used to examined change of endothelial-to-mesenchymal transition (EndoMT) markers and related pathways. Immunofluorescence was used to examine localization and expression of ZO-1 and VE-cadherin. SB203580.was used to block p38 pathway. Unfractionated heparin (UFH) and RAGE siRNA were also used to antagonize the effect of HMGB1.RESULTS:
We showed that HMGB1 induced EndoMT with downregulation of ZO-1 and VE-cadherin at both mRNA and protein levels in HPMECs. We also demonstrated that HMGB1 upregulated endothelial permeability by measuring TEER value and HRP flux. Moreover, HMGB1 activated p38/GSK3ß/Snail signaling pathway and treatment with p38 inhibitor SB203580 abolished its biological effects. In addition, we found that UFH was able to reverse the effect of HMGB1 on EndoMT and endothelial permeability through inhibition of p38 signaling in a dose-dependent manner. We discovered that RAGE, a membrane receptor of HMGB1, transduced p38/Snail pathway to EndoMT. RAGE siRNA inhibited the effect of HMGB1 induced EndoMT in HPMECs.CONCLUSION:
The present study demonstrated that HMGB1 induced EndoMT through RAGE receptor and p38/GSK3ß/Snail pathway. While UFH antagonized HMGB1 and maintained the integrity of the endothelial barrier through p38 inhibition.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Heparina
/
Transdução de Sinais
/
Proteína HMGB1
/
Células Endoteliais
/
Pulmão
/
Anticoagulantes
Limite:
Humans
Idioma:
En
Revista:
Cell Physiol Biochem
Assunto da revista:
BIOQUIMICA
/
FARMACOLOGIA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China