title: Myeloperoxidase-derived hypochlorous acid promotes ox-LDL-induced senescence of endothelial cells through a mechanism involving β-catenin signaling in hyperlipidemia.
abstract: Myeloperoxidase (MPO)-derived product hypochlorous acid (HOCl) is able to induce cellular senescence and MPO is also expressed in endothelial cells besides the well-recognized immune cells. This study aims to clarify the association of endothelium-derived MPO with endothelial senescence in hyperlipidemia. The rats were fed with high-fat diet for 8 weeks to establish a hyperlipidemic model, which showed an increase in plasma lipids, endothelium-derived MPO expression, endothelial senescence and endothelial dysfunction concomitant with a reduction in glycogen synthase kinase 3 beta (GSK-3β) activity and phosphorylated β-catenin (p-β-catenin) level as well as an increase in β-catenin and p53 levels within the endothelium. Next, human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low density lipoprotein (ox-LDL, 100 μg/ml) for 24 h to establish a senescent cell model in vitro. Consistent with the finding in vivo, ox-LDL-induced MPO expression and HUVECs senescence, accompanied by a decrease in GSK-3β activity and p-β-catenin level as well as an increase in HOCl content, β-catenin and p53 levels; these phenomena were attenuated by MPO inhibitor. Replacement of ox-LDL with HOCl could also induce HUVECs senescence and activate the β-catenin/p53 pathway. Based on these observations, we conclude that endothelium-derived MPO is upregulated in hyperlipidemic rats, which may contribute to the accelerated vascular endothelial senescence through a mechanism involving the β-catenin/p53 pathway.
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Yin-Zhuang
authors.initials: YZ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Jie-Jie
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Tin-Bo
authors.initials: TB
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xiong
authors.affiliation: Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha 410013, China.
authors.forename: Xiu-Ju
authors.initials: XJ
authors.lastname: Luo
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: mqilin2004@163.com.
authors.forename: Qi-Lin
authors.initials: QL
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha 410078, China. Electronic address: Junpeng@csu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism* / Q000473:pathology; D006997:Hypochlorous Acid / Q000378:metabolism* / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009195:Peroxidase / Q000737:chemistry / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495268:Ctnnb1 protein, rat; D008055:Lipids; D008077:Lipoproteins, LDL; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C099252:oxidized low density lipoprotein; D006997:Hypochlorous Acid; D009195:Peroxidase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3
keywords: Endothelium; Hyperlipidemia; Hypochlorous acid; Myeloperoxidase; Senescence; β-catenin