title: HMGB1 induces endothelial progenitor cells apoptosis via RAGE-dependent PERK/eIF2α pathway.
abstract: Studies have demonstrated that the high-mobility group 1B protein (HMGB1) could regulate endothelial progenitor cell (EPC) homing, but the effect of HMGB1 on EPC apoptosis and associated mechanisms are still unclear. The aim of this study was to investigate the effects of HMGB1 on EPC apoptosis and the possible involvement of the endoplasmic reticulum (ER) stress pathway. EPC apoptosis was determined by flow cytometry. The expressions of PERK, eIF2α, and CHOP were detected by western blotting. Additionally, the effects of PERK shRNA on the biological behaviors of EPCs were assessed. Our results showed that incubation of EPCs with HMGB1 (0.1-1 μg/ml) for 12-48 h induced apoptosis as well as activated ER stress transducers, as assessed by up-regulating PERK protein expression and eIF2α phosphorylation in a dose or time-dependent manner. Moreover, HMGB1-mediated EPC apoptosis and CHOP expression were dramatically suppressed by PERK shRNA or a specific eIF2α inhibitor (salubrinal). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) markedly inhibited HMGB1-induced EPC apoptosis and ER stress marker protein (PERK, eIF2α, and CHOP) expression levels. Our novel findings suggest that HMGB1 triggered EPC apoptosis in a manner of RAGE-mediated activation of the PERK/eIF2α pathway.
authors.affiliation: Department of Child Health Care, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410008, Hunan, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Xiangya Road 87#, Changsha, 410008, Hunan, China. zhoujipeng0506@163.com.
authors.forename: Ji-Peng
authors.initials: JP
authors.lastname: Zhou
authors.affiliation: Department of Geriatric Medicine, Xiangya Hospital, Central South University, Xiangya Road 87#, Changsha, 410008, Hunan, China. luoying7026@126.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
mesh_terms: D017209:Apoptosis; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: C000593871:AGER protein, human; D015852:Eukaryotic Initiation Factor-2; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D000067759:Receptor for Advanced Glycation End Products; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: Apoptosis; Endoplasmic reticulum stress; Endothelial progenitor cell; High-mobility group 1B