title: Endogenous ceramide contributes to the transcytosis of oxLDL across endothelial cells and promotes its subendothelial retention in vascular wall.
abstract: Oxidized low density of lipoprotein (oxLDL) is the major lipid found in atherosclerotic lesion and elevated plasma oxLDL is recognized to be a risk factor of atherosclerosis. Whether plasma oxLDL could be transported across endothelial cells and initiate atherosclerotic changes remains unknown. In an established in vitro cellular transcytosis model, the present study found that oxLDL could traffic across vascular endothelial cells and further that the regulation of endogenous ceramide production by ceramide metabolizing enzyme inhibitors significantly altered the transcytosis of oxLDL across endothelial cells. It was found that acid sphingomyelinase inhibitor, desipramine (DES), and de novo ceramide synthesis inhibitor, myriocin (MYR), both decreasing the endogenous ceramide production, significantly inhibited the transcytosis of oxLDL. Ceramidase inhibitor, N-oleoylethanolamine (NOE), and sphingomyelin synthase inhibitor, O-Tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt (D609), both increasing the endogenous ceramide production, significantly upregulated the transcytosis of oxLDL. In vivo, injection of fluorescence labeled oxLDL into mice body also predisposed to the subendothelial retention of these oxidized lipids. The observations provided in the present study demonstrate that endogenous ceramide contributes to the transcytosis of oxLDL across endothelial cells and promotes the initiating step of atherosclerosis-the subendothelial retention of lipids in vascular wall.
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Xing
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Bian
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Wanjing
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Xiangli
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Tao
authors.identifier: 0000-0003-1742-1357
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China ; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China.
authors.forename: Si
authors.initials: S
authors.lastname: Jin
mesh_terms: D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D055572:Ceramidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D003891:Desipramine / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009636:Norbornanes; D009829:Oleic Acids / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D057900:Transcytosis / Q000187:drug effects; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001952:Bridged-Ring Compounds; D002518:Ceramides; D063388:Endocannabinoids; D004983:Ethanolamines; D005229:Fatty Acids, Monounsaturated; D008077:Lipoproteins, LDL; D009636:Norbornanes; D009829:Oleic Acids; D013859:Thiocarbamates; D013871:Thiones; C099252:oxidized low density lipoprotein; C033595:N-oleoylethanolamine; C046498:tricyclodecane-9-yl-xanthogenate; D051049:Sphingosine N-Acyltransferase; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase; D013108:Sphingomyelin Phosphodiesterase; D055572:Ceramidases; D003891:Desipramine; C001996:thermozymocidin