Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis (original) (raw)
Related papers
2016
Rationale: NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages and within atherosclerotic lesions, yet its function in atherosclerosis is unknown. Objective: Nur77 regulates the development of monocytes, particularly patrolling Ly6C monocytes that may be involved in resolution of inflammation. We sought to determine how absence of nuclear receptor subfamily 4, group A, member 1 (NR4A1) in hematopoietic cells affected atherosclerosis development. Methods and Results: Nur77/ chimeric mice on a Ldlr/ background showed a 3-fold increase in athero-sclerosis development when fed a Western diet for 20 weeks, despite having a drastic reduction in Ly6C patrolling monocytes. In a second model, mice deficient in both Nur77 and ApoE (ApoE/Nur77/) also showed increased atherosclerosis after 11 weeks of Western diet. Atherosclerosis was associated with a significant change in macrophage polarization toward a proinflammatory phenotype, with high expression of tumor necrosis factor...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2006
Objective-Atherosclerosis is an inflammatory disease in which macrophage activation and lipid loading play a crucial role. In this study, we investigated expression and function of the NR4A nuclear receptor family, comprising Nur77 (NR4A1, TR3), Nurr1 (NR4A2), and NOR-1 (NR4A3) in human macrophages. Methods and Results-Nur77, Nurr1, and NOR-1 are expressed in early and advanced human atherosclerotic lesion macrophages primarily in areas of plaque activation/progression as detected by in situ-hybridization and immunohistochemistry. Protein expression localizes to the nucleus. Primary and THP-1 macrophages transiently express NR4A-factors in response to lipopolysaccharide and tumor necrosis factor ␣. Lentiviral overexpression of Nur77, Nurr1, or NOR-1 reduces expression and production of interleukin (IL)-1 and IL-6 proinflammatory cytokines and IL-8, macrophage inflammatory protein-1␣ and -1 and monocyte chemoattractant protein-1 chemokines. In addition, NR4A-factors reduce oxidized-low-density lipoprotein uptake, consistent with downregulation of scavenger receptor-A, CD36, and CD11b macrophage marker genes. Knockdown of Nur77 or NOR-1 with gene-specific lentiviral short-hairpin RNAs resulted in enhanced cytokine and chemokine synthesis, increased lipid loading, and augmented CD11b expression, demonstrating endogenous NR4A-factors to inhibit macrophage activation, foam-cell formation, and differentiation.
Circulation, 2010
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-␣. 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-␣-induced proinflammatory response of SMCs is inhibited by Nurr1, as reflected by reduced interleukin-1, tumor necrosis factor-␣, 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 Ϫ/Ϫ 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.
Nuclear receptor control of opposing macrophage phenotypes in cardiovascular disease
Frontiers in Bioscience, 2012
Introduction 3. Nuclear receptor control of macrophage activation 3.1. Regulation of macrophage activation by PPARs 3.2. Mineralocorticoid receptor activates proinflammatory macrophage function 3.3. Interaction of nuclear receptors and cytokines 4. Alternatively activated macrophage phenotypes in cardiovascular disease 4.1. Cardiac inflammation, hypertrophy and fibrosis 4.2. Atherosclerosis 4.3. Stroke 5. Heme oxygenase-1 in alternatively activated macrophages 5.1. Atherosclerosis 5.2. Alveolar macrophages and pulmonary hypertension 6. Strategies to study macrophage polarization in disease 7. Summary and perspectives 8. Acknowledgements 9. References
International journal of molecular medicine, 2015
Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments re...
Circulation, 2012
Background-Toll-like receptors (TLRs) have long been considered to be major culprits in the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking. Methods and Results-We used experimental mouse models, human atheroma cultures, and well-established human biobanks to investigate the role of TLR7 in atherosclerosis. We report the unexpected finding that TLR7, a receptor recognizing self-nucleic acid complexes, is protective in atherosclerosis. In Apoe Ϫ/Ϫ mice, functional inactivation of TLR7 resulted in accelerated lesion development, increased stenosis, and enhanced plaque vulnerability as revealed by Doppler ultrasound and/or histopathology. Mechanistically, TLR7 interfered with macrophage proinflammatory responses to TLR2 and TLR4 ligands, reduced monocyte chemoattractant protein-1 production, and prevented expansion of Ly6C hi inflammatory monocytes and accumulation of inflammatory M1 macrophages into developing atherosclerotic lesions. In human carotid endarterectomy specimens TLR7 levels were consistently associated with an M2 anti-inflammatory macrophage signature (interleukin [IL]-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, whereas they were inversely related or unrelated to proinflammatory mediators (IL-12/IL-23, interferon beta, interferon gamma, CD40L) and platelet markers. Moreover, in human atheroma cultures, TLR7 activation selectively suppressed the production of key proatherogenic factors such as monocyte chemoattractant protein-1 and tumor necrosis factor without affecting IL-10. Conclusions-These findings provide evidence for a beneficial role of TLR7 in atherosclerosis by constraining inflammatory macrophage activation and cytokine production. This challenges the prevailing concept that all TLRs are pathogenic and supports the exploitation of the TLR7 pathway for therapy. (Circulation. 2012;126:952-962.)
Macrophage NCOR1 protects from atherosclerosis by repressing a pro-atherogenic PPARγ signature
European Heart Journal, 2019
Aims Nuclear receptors and their cofactors regulate key pathophysiological processes in atherosclerosis development. The transcriptional activity of these nuclear receptors is controlled by the nuclear receptor corepressors (NCOR), scaffolding proteins that form the basis of large corepressor complexes. Studies with primary macrophages demonstrated that the deletion of Ncor1 increases the expression of atherosclerotic molecules. However, the role of nuclear receptor corepressors in atherogenesis is unknown. Methods and results We generated myeloid cell-specific Ncor1 knockout mice and crossbred them with low-density lipoprotein receptor (Ldlr) knockouts to study the role of macrophage NCOR1 in atherosclerosis. We demonstrate that myeloid cell-specific deletion of nuclear receptor corepressor 1 (NCOR1) aggravates atherosclerosis development in mice. Macrophage Ncor1-deficiency leads to increased foam cell formation, enhanced expression of pro-inflammatory cytokines, and atherosclerot...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2000
The absence of the scavenger receptor A (SR-A)-I/II has produced variable effects on atherosclerosis in different murine models. Therefore, we examined whether SR-AI/II deficiency affected atherogenesis in C57BL/6 mice, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, and whether the deletion of macrophage SR-AI/II expression would modulate lesion growth in C57BL/6 mice and LDL receptor (LDLR) Ϫ/Ϫ mice. SR-AI/II-deficient (SR-AI/II Ϫ/Ϫ ) female and male mice on the C57BL/6 background were challenged with a butterfat diet for 30 weeks. No differences were detected in plasma lipids between SR-AI/II Ϫ/Ϫ and SR-AI/II ϩ/ϩ mice, whereas both female and male SR-AI/II Ϫ/Ϫ mice had a tremendous reduction (81% to 86%) in lesion area of the proximal aorta compared with SR-AI/II ϩ/ϩ mice. Next, to analyze the effect of macrophage-specific SR-AI/II deficiency in atherogenesis, female C57BL/6 mice were lethally irradiated, transplanted with SR-AI/II Ϫ/Ϫ or SR-AI/II ϩ/ϩ fetal liver cells, and challenged with the butterfat diet for 16 weeks. In a separate experiment, male LDLR Ϫ/Ϫ mice were reconstituted with SR-AI/II Ϫ/Ϫ or SR-AI/II ϩ/ϩ fetal liver cells and challenged with a Western diet for 10 weeks. No significant differences in plasma lipids and lipoprotein profiles were noted between the control and experimental groups in either experiment. SR-AI/II Ϫ/Ϫ 3 C57BL/6 mice, however, had a 60% reduction in lesion area of the proximal aorta compared with SR-AI/II ϩ/ϩ 3 C57BL/6 mice. A similar level of reduction (60%) in lesion area was noted in the proximal aorta and the entire aorta en face of SR-AI/II Ϫ/Ϫ 3 LDLR Ϫ/Ϫ mice compared with SR-AI/II ϩ/ϩ 3 LDLR Ϫ/Ϫ mice. These results demonstrate in vivo that SR-AI/II expression has no impact on plasma lipid levels and that macrophage SR-AI/II contributes significantly to atherosclerotic lesion formation. (Arterioscler Thromb Vasc