Abstract 5466: Nuclear Receptor Nurr1 in Vascular Smooth Muscle Cells is Protective in In-stent Restenosis

Abstract

Introduction Coronary atherosclerosis is treated by percutaneous coronary intervention (PCI) in combination with stent placement. The major drawback of this intervention is (in-stent) restenosis, which is characterized by activation and excessive proliferation of smooth muscle cells (SMCs). In previous studies we have shown that nuclear receptor Nurr1 inhibits the inflammatory response of macrophages and reduces lipid loading of these cells. In this study we investigated nuclear receptor Nurr1 in SMCs in human and experimental vascular restenosis. Methods and results In a prospective cohort of 601 patients undergoing PCI including stent-placement, we report a strong association of Nurr1 haplotypes with angio-graphic and clinical in-stent restenosis risk (Hazard ratio (HR) 3.1; 95%CI:1.9–5.1 and HR 3.4; 95%CI 1.6–7.1, respectively). Furthermore, Nurr1 is expressed in human in-stent restenosis and induced in cultured human SMCs in response to serum or tumor necrosis factor (TNF)- α -mediated activation. Lentivirus-mediated gain and loss of function experiments in SMCs demonstrated that overexpression of Nurr1 inhibited proliferation, consistent with increased expression of the key cell-cycle inhibitor p27 Kip1 , whereas Nurr1 silencing enhanced SMC growth. The TNF α -induced pro-inflammatory response of SMCs is inhibited by Nurr1 as reflected by reduced interleukin-1 β , TNF α and monocyte chemo-attractant protein-1 expression. In subsequent mouse experiments, Nurr1 was locally expressed in the carotid artery of ApoE−/− mice after wire-induced injury, and we revealed that Nurr1 inhibits SMC-rich lesion formation. In line with this observation, silencing of murine Nurr1 in the vessel wall increased lesion formation. Conclusion Nurr1 haplotypes associate with human in-stent restenosis risk and Nurr1 is expressed in in-stent restenosis. In addition to the anti-inflammatory function of Nurr1 in macrophages, we show that Nurr1 inhibits proliferation and inflammatory responses in SMCs, which explains inhibition of SMC-rich lesion formation in mice. Since small-molecule drugs that enhance the activity of Nurr1 have been identified, we propose this nuclear receptor Nurr1 as an attractive novel target for (local) intervention in restenosis.