TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: crosstalk between NF-κB and PPAR-γ

J Mol Cell Cardiol. 2014 Jul:72:85-94. doi: 10.1016/j.yjmcc.2014.02.012. Epub 2014 Mar 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Atherosclerosis / chemically induced
  • Atherosclerosis / genetics*
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control
  • Benzamides / pharmacology
  • Caveolin 1 / antagonists & inhibitors
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism
  • Caveolin 2 / antagonists & inhibitors
  • Caveolin 2 / genetics
  • Caveolin 2 / metabolism
  • Cinchona Alkaloids / pharmacology
  • Filipin / pharmacology
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Lipoproteins, LDL / antagonists & inhibitors
  • Lipoproteins, LDL / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nitriles / pharmacology
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Proline / analogs & derivatives
  • Proline / pharmacology
  • Pyridines / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, LDL / antagonists & inhibitors
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Signal Transduction
  • Sulfones / pharmacology
  • Thiocarbamates / pharmacology
  • Transcytosis / drug effects*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • 2-chloro-5-nitrobenzanilide
  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • Anilides
  • Benzamides
  • Caveolin 1
  • Caveolin 2
  • Cinchona Alkaloids
  • Lipoproteins, LDL
  • N,N'-dimethylcinchoninium
  • NF-kappa B
  • Nitriles
  • PPAR gamma
  • Pyridines
  • RNA, Small Interfering
  • Receptors, LDL
  • Sulfones
  • T 0070907
  • Thiocarbamates
  • Tumor Necrosis Factor-alpha
  • prolinedithiocarbamate
  • Filipin
  • Proline