Abstract 312: Nuclear Receptor Nur77 Protective in Arterial Remodeling and Vascular Disease
Nur77 is a member of the NR4A subfamily of Nuclear Receptors and is expressed in activated smooth muscle cells (SMCs) and macrophages of human vascular specimen derived from atherosclerotic lesions and in human veins exposed ex vivo to cyclic stretch. NR4A transcription factors have recently been demonstrated to be involved in liver and skeletal muscle metabolism. To reveal the function of Nur77 and its small-molecule activator 6-mercaptopurine (6-MP) in the vessel wall, we performed gain and loss of function experiments in cultured SMCs and monocytes/macrophages as well as in dedicated mouse models. We generated transgenic mice that overexpress Nur77 in arterial SMCs (SM22alpha-promoter) and demonstrated that these mice develop less SMC-rich lesions in response to carotid artery ligation or by placing a loosely fitting cuff around the femoral artery. Moreover, locally applied 6-MP inhibits cuff-induced lesion formation in a Nur77-dependent manner. We now demonstrate that Nur77-transgenic mice develop less arterial remodeling in the contra-lateral carotid upon carotid ligation in comparison to wildtype mice, and we propose that modulation of MMP-expression by Nur77 explains the changed remodeling response of the vessel wall. The crucial role of Nur77 in inflammatory responses in atherosclerotic macrophages is supported by de following observations. Lentiviral overexpression of Nur77 reduces mRNA expression and protein secretion of IL-1β and IL-6, IL-8, MIP-1alpha and -1beta and MCP-1 cytokines. Concerning lipid metabolism, we have demonstrated that Nur77 reduces oxidized-LDL uptake, consistent with downregulation of scavenger receptor-A, CD36 and CD11b macrophage marker genes.
In conclusion: The nuclear receptor Nur77 is expressed in human atherosclerotic lesion SMCs and macrophages and inhibits macrophage foam cell formation and pro-inflammatory cytokine production as well as SMC proliferation and vascular remodeling.