title: miR-21-5p/203a-3p promote ox-LDL-induced endothelial cell senescence through down-regulation of mitochondrial fission protein Drp1.
abstract: This study aims to identify both endothelia-specific/enriched and senescence-associated miRNAs as well as their functions. The rats were fed on high-fat diet to establish a hyperlipidemic model, which showed an increase in plasma lipids and acceleration in endothelial senescence and endothelial dysfunction, accompanied by alterations in 7 endothelia-specific/enriched and senescence-associated miRNAs. Among the 7 selected miRNAs, miR-21-5p and miR-203a-3p were significantly up-regulated in a human umbilical vein endothelial cells (HUVECs) senescent model induced by ox-LDL, consistent with their changes in the hyperlipidemic rats. After performing the bioinformatic analysis, dynamin-related protein 1 (Drp1) was predicted to be a potential target for both miR-21-5p and miR-203a-3p. In ox-LDL-induced senescent HUVECs, Drp1 was significantly down-regulated, concomitant with mitochondrial dysfunctions and the activation of AMPK-p53/p16 pathway, while these phenomena were attenuated by miR-21-5p or miR-203a-3p inhibitor. Luciferase reporter gene assay confirmed a direct interaction between miR-21-5p and Drp1 but not between miR-203a-3p and Drp1. Based on these observations, we conclude that miR-21-5p/203a-3p promote ox-LDL-induced endothelial senescence through down-regulation of Drp1 in a direct or indirect way. Our findings highlight the plasma levels of miR-21-5p/203a-3p may serve as novel biomarkers to evaluate the degree of endothelial senescence in hyperlipidemia.
authors.affiliation: Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
authors.forename: Jie-Jie
authors.initials: JJ
authors.lastname: Zhang
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 Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha 410013, China.
authors.forename: Jing-Jie
authors.initials: JJ
authors.lastname: Peng
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Qi-Lin
authors.initials: QL
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya 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
authors.affiliation: Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Department of Laboratory Medicine, Xiangya School of Medicine, Central South University, Changsha 410013, China. Electronic address: xjluo22@csu.edu.cn.
authors.forename: Xiu-Ju
authors.initials: XJ
authors.lastname: Luo
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D015536:Down-Regulation; D034281:Dynamins / Q000096:biosynthesis*; D020558:GTP Phosphohydrolases / Q000096:biosynthesis*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008077:Lipoproteins, LDL; C546703:MIRN203 microRNA, human; C000604042:MIRN203 microRNA, rat; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C546082:mirn21 microRNA, rat; C099252:oxidized low density lipoprotein; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: Dynamin-related protein 1; Hyperlipidemia; Senescence; miR-203a-3p; miR-21-5p