title: Involvement of NADPH oxidases and non-muscle myosin light chain in senescence of endothelial progenitor cells in hyperlipidemia.
abstract: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) is involved in endothelial dysfunction of hyperlipidemia, and non-muscle myosin regulatory light chain (nmMLC20) is reported to have a transcriptional function in regulation of gene expression. The purposes of this study are to determine whether NOX-derived ROS can promote endothelial progenitor cell (EPC) senescence and whether nmMLC20 can regulate NOX expression through a phosphorylation-dependent manner. The rats were subjected to 8 weeks of high-fat diet feeding to establish a hyperlipidemic model, which showed an increase in plasma lipids and the accelerated senescence and reduced number of circulating EPCs, accompanied by an increase in myosin light chain kinase (MLCK) and NOX activities, p-nmMLC20 level, NOX (NOX2, NOX4) expression, and H2O2 content. Next, EPCs isolated from normal rats were incubated with ox-LDL (100 μg/mL) for 24 h to establish a senescent model in vitro. Consistent with our in vivo findings, ox-LDL treatment increased the senescence of EPCs concomitant with an increase in MLCK and NOX activities, p-nmMLC20 level (in total or nuclear proteins), NOX expression, and H2O2 content; these phenomena were reversed by MLCK inhibitor. NOX inhibitor achieved similar results to that of MLCK inhibitor except that there is no effect on MLCK activity and p-nmMLC20 level. Furthermore, knockdown of nmMLC20, NOX2, or NOX4 led to a down-regulation in NOX and a reduction in ox-LDL-induced EPC senescence. These results suggest that NOX-derived ROS promotes the senescence of circulating EPCs in hyperlipidemia and nmMLC20 may play a transcriptional role in the upregulation of NOX through a phosphorylation-dependent manner.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, Changsha, 410078, China.
authors.forename: Ting-Bo
authors.initials: TB
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, 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, No.110 Xiang-Ya Road, Changsha, 410078, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, Changsha, 410078, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, Changsha, 410078, China.|Hunan Provincial Key Laboratory of Cardiovascular Research, 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 Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China.
authors.forename: Qi-Lin
authors.initials: QL
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, Changsha, 410078, China. Junpeng@csu.edu.cn.|Hunan Provincial Key Laboratory of Cardiovascular Research, School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China. Junpeng@csu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D016922:Cellular Senescence / Q000502:physiology*; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008297:Male; D018994:Myosin Light Chains / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D014230:Triazoles / Q000494:pharmacology
chemical_list: C511179:3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine; D001381:Azepines; D001583:Benzoxazoles; D008055:Lipids; D018994:Myosin Light Chains; D009281:Naphthalenes; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014230:Triazoles; C070571:ML 7; D019255:NADPH Oxidases; D009219:Myosin-Light-Chain Kinase
keywords: Endothelial progenitor cells; Hyperlipidemia; NADPH oxidase (NOX); Non-muscle myosin regulatory light chain (nmMLC20); Oxidative stress