title: HSP27 phosphorylation protects against endothelial barrier dysfunction under burn serum challenge.
abstract: F-actin rearrangement is an early event in burn-induced endothelial barrier dysfunction. HSP27, a target of p38 MAPK/MK2 pathway, plays an important role in actin dynamics through phosphorylation. The question of whether HSP27 participates in burn-related endothelial barrier dysfunction has not been identified yet. Here, we showed that burn serum induced a temporal appearance of central F-actin stress fibers followed by a formation of irregular dense peripheral F-actin in pulmonary endothelial monolayer, concomitant with a transient increase of HSP27 phosphorylation that conflicted with the persistent activation of p38 MAPK/MK2 unexpectedly. The appearance of F-actin stress fibers and transient increase of HSP27 phosphorylation occurred prior to the burn serum-induced endothelial hyperpermeability. Overexpressing phospho-mimicking HSP27 (HSP27(Asp)) reversed the burn serum-induced peripheral F-actin rearrangement with the augmentation of central F-actin stress fibers, and more importantly, attenuated the burn serum-induced endothelial hyperpermeability; such effects were not observed by HSP27(Ala), a non-phosphorylated mutant of HSP27. HSP27(Asp) overexpression also rendered the monolayer more resistant to barrier disruption caused by Cytochalasin D, a chemical reagent that depolymerizes F-actin specifically. Further study showed that phosphatases and sumoylation-inhibited MK2 activity contributed to the blunting of HSP27 phosphorylation during the burn serum-induced endothelial hyperpermeability. Our study identifies HSP27 phosphorylation as a protective response against burn serum-induced endothelial barrier dysfunction, and suggests that targeting HSP27 wound be a promising therapeutic strategy in ameliorating burn-induced lung edema and shock development.
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Huan-bo
authors.initials: HB
authors.lastname: Sun
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Ren
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiao-wei
authors.initials: XW
authors.lastname: Guo
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xu-pin
authors.initials: XP
authors.lastname: Jiang
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Dong-xia
authors.initials: DX
authors.lastname: Zhang
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yue-sheng
authors.initials: YS
authors.lastname: Huang
authors.affiliation: Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: japzhang@aliyun.com.
authors.forename: Jia-ping
authors.initials: JP
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000032:analysis / Q000378:metabolism*; D000328:Adult; D000818:Animals; D002056:Burns / Q000097:blood* / Q000473:pathology; D002460:Cell Line; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010539:Permeability; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D022502:Stress Fibers / Q000378:metabolism / Q000473:pathology; D058207:Sumoylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000199:Actins; D055551:HSP27 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
keywords: Burn; Dephosphorylation; Endothelial permeability; F-actin rearrangement; HSP27; Sumoylation