Abstract 496: Nur77 Nuclear Receptor is a Novel Target for Intervention in Vascular Pathologies.
Introduction: Nur77 belongs to the NR4A subfamily of nuclear orphan receptors and we have shown that this gene is expressed in human atherosclerotic lesions in endothelial cells, smooth muscle cells and macrophages. In addition, Nur77 is expressed in vascular smooth muscle cell pathologies such as in-stent restenosis and vein-graft disease. In the current study we analyzed the expression and function of Nur77 in cultured vascular cells, in THP-1-derived mononcytes/macrophages and in mouse injury models.
Hypothesis: We hypothesized that Nur77 restrains vascular lesion formation.
Methods: Nur77 was overexpressed in vascular cells by lentiviral vehicles and Nur77 knockdown was achieved with gene-specific siRNA. As vein-graft disease models human saphenous vein segments were perfused under arterial pressure and in vitro cultured SMCs were exposed to cyclic stretch. Transgenic mice were generated that overexpress Nur77 under control of the SM22alpha-promoter, which directs expression to arterial smooth muscle cells. Mouse carotid artery ligation and loosely-fitting cuff models were applied.
Results: Nur77 is induced in perfused saphenous vein segments, unless an external stent was applied, indicating that mechanical forces were the key stimulus. Exposure of in vitro cultured SMCs to cyclic stretch resulted in enhanced proliferation of venous SMCs and Nur77 mRNA was induced. Nur77 knockdown resulted in enhanced stretch-induced DNA synthesis, whereas overexpression of Nur77 inhibited proliferation. 6-Mercaptopurine is an agonist of Nur77 and inhibits stretch-induced proliferation in a Nur77-dependent manner. In transgenic mice overexpressing Nur77 in arterial smooth muscle cells both in the carotid artery ligation model and in the loosely fitting femoral artery cuff model smooth cell-rich lesion formation is inhibited. Overexpression of Nur77 in macrophages reduces the atherosclerotic potential of these cells substantially as is shown by reduced inflammatory responses and diminished expression of scavenger receptors.
In conclusion: Nur77 inhibits smooth muscle cell proliferation and macrophage function. Enhancement of local Nur77 activity may open new perspectives to prevent vascular disease.