LOX-1-dependent transcriptional regulation in response to oxidized LDL treatment of human aortic endothelial cells.
Oxidized low-density lipoprotein (OxLDL) has been implicated as a proatherogenic factor with a pathological role in the induction of endothelial dysfunction. Endothelial cells bind and uptake OxLDL primarily through the scavenger receptor lectin-like oxidized-low-density lipoprotein receptor-1 (LOX-1), which is believed to mediate critical effects of OxLDL in endothelial cells. To examine the biological events following LOX-1 activation by OxLDL, we used cDNA microarray analysis to globally analyze gene expression changes induced by OxLDL treatment of human aortic endothelial cell line (HAECT) cells overexpressing LOX-1. Consistent with reported functions of OxLDL, in control HAECT cells, OxLDL elicited gene changes in the oxidative stress pathway and other signaling pathways related to OxLDL. With OxLDL treatment, LOX-1-dependent gene expression changes associated with inflammation, cell adhesion, and signal transduction were observed. The transcripts of a number of cytokines and chemokines were induced, which included interleukin-8, CXCL2, CXCL3, and colony-stimulating factor-3. The secretion of these cytokines was confirmed by enzyme-linked immunosorbent assay analysis. In addition, our data revealed a novel link between LOX-1 and a number of genes, including Delta/notch-like epidermal growth factor repeat containing, stanniocalcin-1, cAMP response element modulator, and dual specificity phosphatase 1. Promoter analysis on the genes that changed as a result of LOX-1 activation by OxLDL allowed us to identify early growth response 1 and cAMP response element-binding protein as potential novel transcription factors that function downstream of LOX-1. Our study has enabled us to elucidate the gene expression changes following OxLDL activation of LOX-1 in endothelial cells and discover novel downstream targets for LOX-1.
Mattaliano
Mark D
MD
Biological Technologies, Wyeth Research, Cambridge, MA 02140, USA.
Huard
Christine
C
Cao
Wei
W
Hill
Andrew A
AA
Zhong
Wenyan
W
Martinez
Robert V
RV
Harnish
Doug C
DC
Paulsen
Janet E
JE
Shih
Heather H
HH
D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D016000:Cluster Analysis; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014161:Transduction, Genetic
D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D014157:Transcription Factors; C099252:oxidized low density lipoprotein