PMID- 24594319 OWN - NLM STAT- MEDLINE DCOM- 20150113 LR - 20140527 IS - 1095-8584 (Electronic) IS - 0022-2828 (Linking) VI - 72 DP - 2014 Jul TI - TNF-alpha promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: crosstalk between NF-kappaB and PPAR-gamma. PG - 85-94 LID - S0022-2828(14)00062-5 [pii] LID - 10.1016/j.yjmcc.2014.02.012 [doi] AB - Tumor necrosis factor-alpha (TNF-alpha) is an established pro-atherosclerotic factor, but the mechanism is not completely understood. We explored whether TNF-alpha could promote atherosclerosis by increasing the transcytosis of lipoproteins (e.g., LDL) across endothelial cells and how NF-kappaB and PPAR-gamma were involved in this process. TNF-alpha 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-alpha were substantially blocked not only by transcytosis inhibitors, but also by NF-kappaB inhibitors and PPAR-gamma inhibitors. In ApoE(-/-) mice, both NF-kappaB and PPAR-gamma inhibitors alleviated the early atherosclerotic changes promoted by TNF-alpha. NF-kappaB and PPAR-gamma inhibitors down-regulated the transcriptional activities of NF-kappaB and PPAR-gamma induced by TNF-alpha. Furthermore, cross-binding activity assay revealed that NF-kappaB and PPAR-gamma could form an active transcription factor complex containing both the NF-kappaB P65 subunit and PPAR-gamma. The increased expressions of LDL transcytosis-related proteins (LDL receptor and caveolin-1, -2) stimulated by TNF-alpha were also blocked by both NF-kappaB inhibitors and PPAR-gamma inhibitors. TNF-alpha promotes atherosclerosis by increasing the LDL transcytosis across endothelial cells and thereby facilitating LDL retention in vascular walls. In this process, NF-kappaB and PPAR-gamma are activated coordinately to up-regulate the expression of transcytosis-related proteins. These observations suggest that inhibitors of either NF-kappaB or PPAR-gamma can be used to target atherosclerosis. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Zhang, Youzhi AU - Zhang Y AD - 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. FAU - Yang, Xiaoyan AU - Yang X AD - 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. FAU - Bian, Fang AU - Bian F AD - 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. FAU - Wu, Pinhui AU - Wu P AD - 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. FAU - Xing, Shasha AU - Xing S AD - 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. FAU - Xu, Gao AU - Xu G AD - 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. FAU - Li, Wenjing AU - Li W AD - 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. FAU - Chi, Jiangyang AU - Chi J AD - 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. FAU - Ouyang, Changhan AU - Ouyang C AD - 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. FAU - Zheng, Tao AU - Zheng T AD - 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. FAU - Wu, Dan AU - Wu D AD - 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. FAU - Zhang, Yonghui AU - Zhang Y AD - 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. FAU - Li, Yongsheng AU - Li Y AD - 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. FAU - Jin, Si AU - Jin S AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140302 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (2-chloro-5-nitrobenzanilide) RN - 0 (3-(4-methylphenylsulfonyl)-2-propenenitrile) RN - 0 (Anilides) RN - 0 (Benzamides) RN - 0 (Caveolin 1) RN - 0 (Caveolin 2) RN - 0 (Cinchona Alkaloids) RN - 0 (Lipoproteins, LDL) RN - 0 (N,N'-dimethylcinchoninium) RN - 0 (NF-kappa B) RN - 0 (Nitriles) RN - 0 (PPAR gamma) RN - 0 (Pyridines) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, LDL) RN - 0 (Sulfones) RN - 0 (T 0070907) RN - 0 (Thiocarbamates) RN - 0 (Tumor Necrosis Factor-alpha) RN - 135467-92-4 (prolinedithiocarbamate) RN - 87Z59R7D14 (Filipin) RN - 9DLQ4CIU6V (Proline) SB - IM MH - Anilides/pharmacology MH - Animals MH - Atherosclerosis/chemically induced/*genetics/pathology/prevention & control MH - Benzamides/pharmacology MH - Caveolin 1/antagonists & inhibitors/genetics/metabolism MH - Caveolin 2/antagonists & inhibitors/genetics/metabolism MH - Cinchona Alkaloids/pharmacology MH - Filipin/pharmacology MH - Gene Expression Regulation MH - Human Umbilical Vein Endothelial Cells/cytology/drug effects/metabolism MH - Humans MH - Lipoproteins, LDL/antagonists & inhibitors/*metabolism MH - Mice MH - Mice, Knockout MH - NF-kappa B/antagonists & inhibitors/genetics/*metabolism MH - Nitriles/pharmacology MH - PPAR gamma/antagonists & inhibitors/genetics/*metabolism MH - Proline/analogs & derivatives/pharmacology MH - Pyridines/pharmacology MH - RNA, Small Interfering/genetics/metabolism MH - Receptors, LDL/antagonists & inhibitors/genetics/metabolism MH - Signal Transduction MH - Sulfones/pharmacology MH - Thiocarbamates/pharmacology MH - Transcytosis/*drug effects MH - Tumor Necrosis Factor-alpha/metabolism/*pharmacology OTO - NOTNLM OT - Atherosclerosis OT - LDL OT - NF-kappaB OT - PPAR-gamma OT - TNF-alpha EDAT- 2014/03/07 06:00 MHDA- 2015/01/15 06:00 CRDT- 2014/03/06 06:00 PHST- 2013/08/03 00:00 [received] PHST- 2014/02/21 00:00 [revised] PHST- 2014/02/24 00:00 [accepted] PHST- 2014/03/06 06:00 [entrez] PHST- 2014/03/07 06:00 [pubmed] PHST- 2015/01/15 06:00 [medline] AID - S0022-2828(14)00062-5 [pii] AID - 10.1016/j.yjmcc.2014.02.012 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2014 Jul;72:85-94. doi: 10.1016/j.yjmcc.2014.02.012. Epub 2014 Mar 2.