NR4A Orphan Nuclear Receptors in Cardiovascular Biology

The NR4A orphan nuclear receptor subfamily is comprised of the highly homologous receptors Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3). These evolutionarily conserved and ancient receptors function as ligand-independent transcription factors that regulate the expression of overlapping target genes. As early response genes, the basal expression level of these receptors is low but rapidly induced as a result of changes in environmental cues. The transcriptional activity of these receptors is primarily regulated by gene induction and posttranslational modifications of the receptor including phosphorylation. NR4A receptors were initially identified in the brain and early functional studies suggested a role for these receptors in signal- and cell-specific stimulation of both apoptosis and proliferation. More recent studies have revealed much broader functions of these orphan receptors including the regulation of genes involved in cancer, metabolism, energy balance, atherosclerosis, and vascular remodeling. In this review, we will discuss our current understanding of the molecular biology of NR4A receptors and summarize recent studies suggesting an important role of these orphan receptors in vascular biology.