Activated protein C inhibits lipopolysaccharide‐mediated acetylation and secretion of high‐mobility group box 1 in endothelial cells
Author(s): ,
Xiaofeng Cai
Affiliations:
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA
,
Indranil Biswas
Affiliations:
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA
,
Sumith R. Panicker
Affiliations:
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA
,
Hemant Giri
Affiliations:
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA
Alireza R. Rezaie
Affiliations:
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, USA
Correspondence: Alireza R. Rezaie, Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA|Tel: +1 405 271 4711|E‐mail: Ray-Rezaie@omrf.org
ISTH Academy. R. Rezaie A. May 1, 2019; 273613
Alireza R. Rezaie
Alireza  R. Rezaie
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Background
Activated protein C (APC) inhibits high‐mobility group box 1 (HMGB1) signaling and its lipopolysaccharide (LPS)‐mediated release by endothelial protein C receptor (EPCR)‐dependent activation of protease‐activated receptor 1 (PAR1) in endothelial cells. Post‐translational acetylation is known to modulate the subcellular localization of HMGB1, and its hyperacetylated form is translocated to the cytoplasm of innate immune cells before being secreted into the extracellular space.
Objective
To determine whether APC inhibits LPS‐mediated HMGB1 secretion from endothelial cells by modulating its acetylation status.
Methods
The subcellular localization of HMGB1 in LPS‐treated endothelial cells was monitored in the absence and presence of APC by western blot analysis of fractionated cell lysates and confocal immunofluorescence microscopy.
Results
Both western blot and immunofluorescence data indicated that APC effectively inhibits LPS‐mediated translocation of HMGB1 from the nucleus to the cytoplasm by EPCR‐dependent and PAR1‐dependent mechanisms. When EPCR was ligated by the Gla‐domain of protein C/APC, thrombin also inhibited LPS‐mediated HMGB1 translocation. Further studies revealed that APC inhibits the translocation of HMGB1 from the nucleus to the cytoplasm by inhibiting LPS‐mediated hyperacetylation of HMGB1 by (de)acetylating enzymes. Furthermore, the translocated HMGB1 was found to be associated with lysosome‐associated membrane protein 1 in LPS‐treated endothelial cells. The in vivo relevance of these findings was investigated in the mouse cremaster muscle, and this demonstrated that both wild‐type APC and a signaling‐selective mutant of APC inhibit LPS‐mediated HMGB1 expression and translocation in CD31‐positive endothelial cells.
Conclusion
These results suggest that APC inhibits LPS‐mediated cytoplasmic translocation and secretion of HMGB1 in endothelial cells by epigenetic mechanisms.
Keyword(s)
acetylation, activated protein C, endothelial protein C receptor, HMGB1, protease‐activated receptor 1
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