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.
Keywords:
Atherosclerosis; LDL; NF-κB; PPAR-γ; TNF-α.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anilides / pharmacology
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Animals
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Atherosclerosis / chemically induced
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Atherosclerosis / genetics*
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Atherosclerosis / pathology
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Atherosclerosis / prevention & control
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Benzamides / pharmacology
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Caveolin 1 / antagonists & inhibitors
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Caveolin 1 / genetics
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Caveolin 1 / metabolism
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Caveolin 2 / antagonists & inhibitors
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Caveolin 2 / genetics
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Caveolin 2 / metabolism
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Cinchona Alkaloids / pharmacology
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Filipin / pharmacology
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Gene Expression Regulation
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Lipoproteins, LDL / antagonists & inhibitors
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Lipoproteins, LDL / metabolism*
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Mice
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Mice, Knockout
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Nitriles / pharmacology
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PPAR gamma / antagonists & inhibitors
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PPAR gamma / genetics
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PPAR gamma / metabolism*
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Proline / analogs & derivatives
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Proline / pharmacology
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Pyridines / pharmacology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, LDL / antagonists & inhibitors
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Receptors, LDL / genetics
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Receptors, LDL / metabolism
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Signal Transduction
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Sulfones / pharmacology
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Thiocarbamates / pharmacology
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Transcytosis / drug effects*
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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2-chloro-5-nitrobenzanilide
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3-(4-methylphenylsulfonyl)-2-propenenitrile
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Anilides
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Benzamides
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Caveolin 1
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Caveolin 2
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Cinchona Alkaloids
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Lipoproteins, LDL
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N,N'-dimethylcinchoninium
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NF-kappa B
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Nitriles
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PPAR gamma
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Pyridines
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RNA, Small Interfering
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Receptors, LDL
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Sulfones
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T 0070907
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Thiocarbamates
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Tumor Necrosis Factor-alpha
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prolinedithiocarbamate
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Filipin
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Proline