Expression of transcriptional repressor ATF3/LRF1 in human atherosclerosis: colocalization and possible involvement in cell death of vascular endothelial cells.
Vascular endothelial cell death contributes to the progression of atherosclerotic lesion, and several transcriptional regulators are involved in the process. Activating transcription factor 3/liver regenerating factor-1 (ATF3/LRF-1), a stress-inducible transcriptional repressor, was shown to be highly expressed in vascular endothelial cells and macrophages of human atherosclerotic lesions by immunohistological assay. The expression was colocalized in these cells which were positive for TdT-mediated dUTP nick-end labeling (TUNEL) and annexin V. Treatment of human umbilical vein endothelial cells (HUVECs) by tumor necrosis factor (TNF)-alpha, oxidized low density lipoprotein (oxLDL), and lysophosphatidylcholine (LPC) rapidly induced ATF3/LRF-1, which showed an increased DNA binding to the consensus ATF/CRE sequence by supershift of gel shift assay. Flow cytometry analysis and immunostaining analysis with TUNEL assay showed that ATF3/LRF-1 was highly expressed in cell death induced by these agents. Moreover, antisense ATF3/LRF-1 cDNA partly suppressed the cell death induced by TNF-alpha, oxLDL, and LPC. From these results, it is indicated that ATF3/LRF-1 is one of the immediate early response genes in vascular endothelial cells in response to atherogenic stimuli, and may play a role in the endothelial cell death associated with atherogenesis.
Nawa
Tigre
T
Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Nawa
Makiko T
MT
Adachi
Mimi T
MT
Uchimura
Isao
I
Shimokawa
Reiko
R
Fujisawa
Kazuhiko
K
Tanaka
Akira
A
Numano
Fujio
F
Kitajima
Shigetaka
S
D051700:Activating Transcription Factor 3; D001161:Arteriosclerosis / Q000209:etiology* / Q000473:pathology*; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011336:Probability; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051700:Activating Transcription Factor 3; D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C068616:liver regeneration factor 1