Involvement of transcription factors in plasma HDL protection against TNF-alpha-induced vascular cell adhesion molecule-1 expression.
Plasma HDL has been reported to protect against the initial development of inflammatory atherosclerosis. Although cellular and molecular mechanisms of this HDL protection are not fully understood, they may involve prevention of the endothelial trafficking of circulating leukocytes via its down-regulation of inflammatory genes. To test this hypothesis, HDL inhibition of monocyte adherence to the endothelium and of the expression of vascular cell adhesion molecule-1 (VCAM-1) and its transcriptional regulatory mechanism were elucidated in human umbilical vein endothelial cells (HUVECs) stimulated by pro-inflammatory TNF-alpha. Plasma HDL (1mg/ml apo A1) markedly prevented the monocyte adhesion to TNF-alpha-activated HUVECs with blunting the increased expression levels of VCAM-1 protein and its mRNA at a maximal TNF-alpha stimulation. Electrophoretic mobility shift assay showed that in the activated HUVECs HDL substantially inhibited DNA binding activities of transcription factors of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) that have binding sites in the promoter region of the VCAM-1 gene. In addition, immunocytochemical staining analysis confirmed that HDL inhibited TNF-alpha-induced VCAM-1 expression via reduced nuclear translocation of NF-kappaB. These results suggest that HDL down-regulates the expression of VCAM-1 gene in TNF-alpha-activated HUVECs at transcriptional levels via blunted translocation and transactivation of NF-kappaB and AP-1 transcription factors. Plasma HDL may block the initial atherosclerotic process via inhibited monocyte adhesion to the endothelium, which is independent of modulating the cholesterol reverse transport of plasma HDL.
Park
Sung-Hee
SH
Division of Life Sciences and Institute of Environment and Life Science, Hallym University, #1 Ockchon-dong, 200-702, Kangwon-do, Chuncheon, South Korea.
Park
Jung Han Yoon
JH
Kang
Jung-Sook
JS
Kang
Young-Hee
YH
D002448:Cell Adhesion / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D008075:Lipoproteins, HDL; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1