Nuclear Receptor Nurr1 Is Expressed In and Is Associated With Human Restenosis and Inhibits Vascular Lesion Formation In Mice Involving Inhibition of Smooth Muscle Cell Proliferation and Inflammation

Abstract

Background— Restenosis is the major drawback of percutaneous coronary interventions involving excessive activation and proliferation of vascular smooth muscle cells (SMCs). The nuclear receptor Nurr1 is an early response gene known mainly for its critical role in the development of dopamine neurons. In the present study, we investigated Nurr1 in human and experimental vascular restenosis. Methods and Results— In a prospective cohort of 601 patients undergoing percutaneous coronary intervention, including stent placement, we found a strong association between Nurr1 haplotypes and in-stent restenosis risk. Furthermore, Nurr1 is specifically expressed in human in-stent restenosis and induced in cultured human SMCs in response to serum or tumor necrosis factor-α. 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 tumor necrosis factor-α–induced proinflammatory response of SMCs is inhibited by Nurr1, as reflected by reduced interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1 expression. Consistent with our in vitro data, endogenous Nurr1 reduced wire injury–induced proliferation and vascular lesion formation in carotid arteries of ApoE −/− mice. Conclusion— Nurr1 haplotypes are associated with human restenosis risk, and Nurr1 is expressed in human in-stent restenosis. In SMCs, Nurr1 inhibits proliferation and inflammatory responses, which explains the inhibition of SMC-rich lesion formation in mice. The recently identified small-molecule drugs that enhance the activity of Nurr1 reveal this nuclear receptor as an attractive novel target for (local) intervention in restenosis.

Peroxisome Proliferator-activated Receptor γ Coactivator 1β (PGC-1β) Protein Attenuates Vascular Lesion Formation by Inhibition of Chromatin Loading of Minichromosome Maintenance Complex in Smooth Muscle Cells

“…Proliferation and migration of VSMCs stimulated by growth factors and cytokines, which are released by platelets and VSMCs, are essential for neointimal development upon injury. Recently, evidence from others and our own studies has shown that transcription factors play a critical role in the regulation of VSMC proliferation and migration (3)(4)(5)(6)(7)(8).…”

CCN4 Regulates Vascular Smooth Muscle Cell Migration and Proliferation

“…Tumor necrosis factor (TNF)-α is one of the pro-inflammatory cytokines that mediate a wide range of immune and inflammatory responses and have been found to be involved in the development of post-PCI restenosis and atherosclerosis (Bonta et al, 2010;Maddaluno et al, 2012). It has been reported that TNF-α stimulates the proliferation and migration of VSMCs, and is up-regulated at the site of vascular injury and in atheros- clerotic plaque specimens (Gupta et al, 2012;Wang et al, 2009b).…”

High Cytoplasmic Expression of the Orphan Nuclear Receptor NR4A2 Predicts Poor Survival in Nasopharyngeal Carcinoma

“…NR4A2 is an orphan nuclear receptor and a member of the nerve growth factor I-B subfamily of transcription factors with no known endogenous ligand or stimulator. It is a key regulatory molecule in a number of biological processes, including regulation of proliferation, apoptosis, migration and differentiation in a cell type-specific manner (Ke et al, 2004;Bonta et al, 2010;Lee et al, 2010;Sirin et al, 2010;Maijenburg et al, 2012). Recently, the oncogenic activities of NR4A2 are emerging.…”