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

Tumor necrosis factor-a (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-kappa B 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-kappa B inhibitors and PPAR-gamma inhibitors. In ApoE(-/-) mice, both NF-kappa B and PPAR-gamma inhibitors alleviated the early atherosclerotic changes promoted by TNF-alpha. NF-kappa B and PPAR-gamma inhibitors down-regulated the transcriptional activities of NF-kappa B and PPAR-gamma induced by TNF-alpha. Furthermore, cross-binding activity assay revealed that NF-kappa B and PPAR-gamma could form an active transcription factor complex containing both the NF-kappa B 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-kappa B 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-kappa B and PPAR-gamma are activated coordinately to up-regulate the expression of transcytosis-related proteins. These observations suggest that inhibitors of either NF-kappa B or PPAR-gamma can be used to target atherosclerosis. (C) 2014 Elsevier Ltd. All rights reserved.