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

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

Author information

1
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.
2
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.

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

PMID:
24594319
DOI:
10.1016/j.yjmcc.2014.02.012
[Indexed for MEDLINE]

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