Abstract 975: Regulation of the Activity of Nuclear Receptors by the Interferon Inducible Gene 12 Modulates the Vascular Response Injury
Previously we and others showed that inflammatory mechanisms play a key role in the process of neointimal formation and restenosis. In vascular inflammation the orphan nuclear receptor NR4A1 is upregulated by inflammatory cytokines and its activity seems to be rather protective, because mice deficient in NR4A1 exhibit a higher degree of restenosis upon carotid artery ligation. In search for other factors regulated during vascular injury, we found the interferon inducible gene 12 (ISG12, IFI27) that interacts and co-localizes at the nuclear membrane with NR4A1, PPARα and RXRα in a mammalian cells. ISG12 is up-regulated by interferons in endothelial and smooth muscle cells and human monocytes. Over-expression of ISG12 down-regulates transcriptional activities of the orphan nuclear receptor NR4A1 and NR4A2 and of the adopted nuclear receptors PPARα and PPARγ, an effect that is likely due to nuclear cytoplasmic distribution. With respect to the NR4A family this effect is specific to NR4A1 and NR4A2 while NR4A3, is barely affected. Therefore in vascular cells the ISG12 effect is rather restricted to NR4A1 and upregulation of ISG12 upon vascular injury would reduce the “beneficial” effect of NR4A1. When ISG12 upregulation is absent as in ISG12 deficient mice generated by us transcriptional activities of these nuclear receptors are not impaired as shown in reporter assay in mouse embryonic fibroblasts. While these mice exhibit no gross phenotype without challenge, the protective effects of NR4A1 are fully appreciated in a vascular injury model. Consistently, ISG12 deficient mice are resistant to restenosis upon carotid artery ligation while mice double deficient in ISG12 and NR4A1 are not. Human genetics studies support a possible importance of ISG12 as we could show a strong association between an ISG12 SNP in the 3′UTR and the presence of hypercholesterolemia, diabetes type 2 and stroke. ISG12 might therefore represent a target for novel therapeutic strategies for the treatment of vascular diseases.