Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transcriptional regulation by Oct-1 in human endothelial cells: implications for atherosclerosis.
LOX-1, a receptor for ox-LDL (oxidized low-density lipoprotein), has recently been determined to play a critical role in the progression of atherosclerosis. LOX-1 expression (mRNA and protein) has been shown to be up-regulated by pro-atherogenic stimuli, such as ox-LDL and Ang II (angiotensin II). However, the molecular mechanisms of these up-regulations are unclear. In the present study, we explored LOX-1 transcriptional promoter activation in response to ox-LDL and Ang II. Under basal states, LOX-1 core promoter (LOX-1 -35/+36) was found to be sufficient for its basal activity in HCAECs (human coronary artery endothelial cells). More importantly, we found that ox-LDL (60 microg/ml for 24 h) induced LOX-1 promoter activity significantly and that a 105 bp fragment (between nt -1599 and -1494) was required for this activation. Within this 106 bp fragment, there is a potential binding motif for the transcription factor Oct-1 (octamer-1). By electrophoretic mobility-shift assay, we observed the activation of Oct-1 by ox-LDL. The critical role of Oct-1 in ox-LDL-induced LOX-1 promoter activation was further confirmed by mutagenesis assay. For comparison, we also examined LOX-1 promoter activation in response to Ang II (1 micromol/l for 24 h). Interestingly, another promoter region, between nt -2336 and -1990, was required for Ang II-induced LOX-1 promoter activation. In conclusion, the present study strongly suggests that ox-LDL, by activating Oct-1, induces LOX-1 promoter activation. Furthermore, this study suggests that while ox-LDL and Ang II both induce LOX-1 expression in HCAECs, the underlying mechanisms of promoter activation are different from each other.
Chen
Jiawei
J
Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
Liu
Yong
Y
Liu
Hongmei
H
Hermonat
Paul L
PL
Mehta
Jawahar L
JL
D000804:Angiotensin II / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D001665:Binding Sites; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D009154:Mutation; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000235:genetics*; D014158:Transcription, Genetic
D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D050811:Octamer Transcription Factor-1; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D000804:Angiotensin II