The Nuclear Orphan Receptors Nur77 And Nor-1 Are Novel Mediators Of The Inflammatory Response Induced By Oxidized Phospholipids

Nur77 and NOR-1, both members of the NR4A subgroup of nuclear receptors, are highly expressed in atherosclerotic lesions. However, factors responsible for NR4A expression are poorly characterized. LDL-derived phospholipid oxidation products of 1-palmitoyl-2-arachidonoyl-sn-3-glycero-phosphorylcholine (OxPAPC) have been shown to be present in the atherosclerotic plaque and induce a large set of pro- and anti-inflammatory genes, rendering them candidate triggers of the inflammatory process in atherosclerosis. Here, we show induction of NOR-1 and Nur77 mRNA and protein expression by OxPAPC in human umbilical venous endothelial cells (HUVEC) in a time and concentration-dependent manner, whereas native phospholipids have no effect. Using transient transfection assays and different NOR-1 promoter-driven luciferase constructs, we demonstrate the direct transcriptional regulation of NOR-1 by OxPAPC. Moreover, utilization of Nur77 and NOR-1 siRNA revealed a critical role of these nuclear receptors in the transcriptional regulation of a subset of OxPAPC-induced genes including vascular endothelial growth factor and the anti-inflammatory gene heme oxygenase-1. Thus, nuclear orphan receptors of the NR4A family mediate the effects of lipid oxidation products on the transcriptional level and might be involved in the initiation of chronic inflammatory disorders and tissue repair mechanisms.