title: TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: crosstalk between NF-κB and PPAR-γ.
abstract: Tumor necrosis factor-α (TNF-α) is an established pro-atherosclerotic factor, but the mechanism is not completely understood. We explored whether TNF-α could promote atherosclerosis by increasing the transcytosis of lipoproteins (e.g., LDL) across endothelial cells and how NF-κB and PPAR-γ were involved in this process. TNF-α significantly increased the transcytosis of LDL across human umbilical vein endothelial cells (HUVECs) and stimulated an increase of subendothelial retention of LDL in vascular walls. These effects of TNF-α were substantially blocked not only by transcytosis inhibitors, but also by NF-κB inhibitors and PPAR-γ inhibitors. In ApoE(-/-) mice, both NF-κB and PPAR-γ inhibitors alleviated the early atherosclerotic changes promoted by TNF-α. NF-κB and PPAR-γ inhibitors down-regulated the transcriptional activities of NF-κB and PPAR-γ induced by TNF-α. Furthermore, cross-binding activity assay revealed that NF-κB and PPAR-γ could form an active transcription factor complex containing both the NF-κB P65 subunit and PPAR-γ. The increased expressions of LDL transcytosis-related proteins (LDL receptor and caveolin-1, -2) stimulated by TNF-α were also blocked by both NF-κB inhibitors and PPAR-γ inhibitors. TNF-α promotes atherosclerosis by increasing the LDL transcytosis across endothelial cells and thereby facilitating LDL retention in vascular walls. In this process, NF-κB and PPAR-γ are activated coordinately to up-regulate the expression of transcytosis-related proteins. These observations suggest that inhibitors of either NF-κB or PPAR-γ can be used to target atherosclerosis.
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 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, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 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, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Pinhui
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 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, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Gao
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, 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, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Chi
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Changhan
authors.initials: C
authors.lastname: Ouyang
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; The Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China. Electronic address: Jinsi@mail.hust.edu.cn.
authors.forename: Si
authors.initials: S
authors.lastname: Jin
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D001549:Benzamides / Q000494:pharmacology; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051243:Caveolin 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002930:Cinchona Alkaloids / Q000494:pharmacology; D005372:Filipin / Q000494:pharmacology; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D057900:Transcytosis / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000813:Anilides; D001549:Benzamides; D051242:Caveolin 1; D051243:Caveolin 2; D002930:Cinchona Alkaloids; D008077:Lipoproteins, LDL; C511298:N,N'-dimethylcinchoninium; D016328:NF-kappa B; D009570:Nitriles; D047495:PPAR gamma; D011725:Pyridines; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D013450:Sulfones; C458508:T 0070907; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D005372:Filipin; D011392:Proline
keywords: Atherosclerosis; LDL; NF-κB; PPAR-γ; TNF-α