title: Hypoxic trophoblast HMGB1 induces endothelial cell hyperpermeability via the TRL-4/caveolin-1 pathway.
abstract: High mobility group box 1 (HMGB1) plays an important role in the pathologic processes of endothelial permeability under oxidative stress. Trophoblast oxidative stress has been implicated in the pathophysiology of preeclampsia (PE). HMGB1 serum levels are increased in PE. However, the potential roles of HMGB1 in endothelial permeability in PE remain unclear. We assessed the effects of the hypoxic trophoblast on the permeability of the endothelial monolayer. Our results showed that the hypoxic trophoblast displayed higher HMGB1 mRNA, intracellular HMGB1 protein, and HMGB1 in conditioned medium than those of the normoxic trophoblast did. The hypoxic trophoblast conditioned medium increased the endothelial monolayer permeability and increased TLR 4 and caveolin-1 (CAV-1) protein expression in endothelial cells, which was inhibited by glycyrrhizic acid and HMGB1 small interfering RNA transfection to trophoblasts before hypoxia. The increased endothelial permeability induced by hypoxic trophoblast conditioned medium could be inhibited with TLR4 or CAV-1 gene silencing in endothelial cells. Immunoprecipitation showed that CAV-1 and TLR4 are colocalized in HUVECs and C57BL/6 mouse kidney. TLR4 small interfering RNA suppressed CAV-1 protein expression in endothelial cells upon stimulation of hypoxic trophoblast conditioned medium or HMGB1. We conclude that hypoxic trophoblasts play an important role in the mechanism of general edema (including protein urine) in PE via increasing endothelial monolayer permeability through the HMGB1/TLR4/CAV-1 pathway.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiaotong University No. 6 People's Hospital, Shanghai 200233, China;
authors.forename: Rongzhen
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Center for Vascular and Translational Medicine, the College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China;
authors.forename: Jingjing
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Center for Vascular and Translational Medicine, the College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China;
authors.forename: Dandan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Center for Vascular and Translational Medicine, the College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China;
authors.forename: Jiemei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Vascular and Translational Medicine, the College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China;
authors.forename: Qingde
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiaotong University No. 6 People's Hospital, Shanghai 200233, China;
authors.forename: Yincheng
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiaotong University No. 6 People's Hospital, Shanghai 200233, China;
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiaotong University No. 6 People's Hospital, Shanghai 200233, China;
authors.forename: Minfang
authors.initials: M
authors.lastname: Tao
authors.affiliation: Center for Vascular and Translational Medicine, the College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China;
authors.forename: Aibin
authors.initials: A
authors.lastname: Xia
authors.affiliation: Center for Vascular and Translational Medicine, the College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China;
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Center for Vascular and Translational Medicine, the College of Pharmacy, and The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; afychen@yahoo.com.
authors.forename: Alex F
authors.initials: AF
authors.lastname: Chen
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D017077:Culture Media, Conditioned; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019695:Glycyrrhizic Acid