TNF-alpha promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: Crosstalk between NF-kappaB and PPAR-gamma

摘要

Tumor necrosis factor-alpha (TNF-alpha) is an established pro-atherosderotic factor, but the mechanism is not completely understood. We explored whether TNF-a 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-a 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-a 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-a. NF-kappaB and PPAR-gamma inhibitors down-regulated the transcriptional activities of NF-kappaB and PPAR-gamma induced by TNF-a. 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-a were also blocked by both NF-kappaB inhibitors and PPAR-gamma inhibitors. TNF-a 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.