Submitted on October 7, 2008
Revised on February 2, 2009
Accepted on March 5, 2009
LOX-1-dependent transcriptional regulation in response to oxidized LDL treatment of human aortic endothelial cells
Mark D Mattaliano1, Christine Huard1, Wei Cao1, Andrew A Hill1, Wenyan Zhong1, Robert V Martinez1, Douglas C Harnish1, Janet E Paulsen1, and Heather H Shih1*
1 Wyeth
* To whom correspondence should be addressed. E-mail: Hshih{at}wyeth.com.
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 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 over-expressing 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 IL8, CXCL2, CXCL3, and CSF3. The secretion of these cytokines was confirmed by ELISA analysis. In addition, our data revealed a novel link between LOX-1 and a number of genes including DNER, STC1, CREM, and DUSP1. Promoter analysis on the genes that changed as a result of LOX-1 activation by OxLDL allowed us to identify EGR1 and CREB 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.
