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 (original) (raw)

Activation of nuclear receptor Nur77 by 6-mercaptopurine inhibits smooth muscle cell proliferation

Vascular Pharmacology, 2006

Background-Restenosis is a common complication after percutaneous coronary interventions and is characterized by excessive proliferation of vascular smooth muscle cells (SMCs). We have shown that the nuclear receptor Nur77 protects against SMC-rich lesion formation, and it has been demonstrated that 6-mercaptopurine (6-MP) enhances Nur77 activity. We hypothesized that 6-MP inhibits neointima formation through activation of Nur77. Methods and Results-It is demonstrated that 6-MP increases Nur77 activity in cultured SMCs, which results in reduced [ 3 H]thymidine incorporation, whereas Nur77 small interfering RNA knockdown partially restores DNA synthesis. Furthermore, we studied the effect of 6-MP in a murine model of cuff-induced neointima formation. Nur77 mRNA is upregulated in cuffed arteries, with optimal expression after 6 hours and elevated expression up to 7 days after vascular injury. Local perivascular delivery of 6-MP with a drug-eluting cuff significantly inhibits neointima formation in wild-type mice. Locally applied 6-MP does not affect inflammatory responses or apoptosis but inhibits expression of proliferating cell nuclear antigen and enhances protein levels of the cell-cycle inhibitor p27 Kip1 in the vessel wall. An even stronger inhibition of neointima formation in response to local 6-MP delivery was observed in transgenic mice that overexpressed Nur77. In contrast, 6-MP does not alter lesion formation in transgenic mice that overexpress a dominant-negative variant of Nur77 in arterial SMCs, which provides evidence for the involvement of Nur77-like factors. Conclusions-Enhancement of the activity of Nur77 by 6-MP protects against excessive SMC proliferation and SMC-rich neointima formation. We propose that activation of the nuclear receptor Nur77 is a rational approach to treating in-stent restenosis. (Circulation. 2007;115:493-500.) From the Gaubius Laboratory, TNO-Quality of Life (N.M.M.P., M.R.d.V., P.H.A.Q.), Leiden; the Departments of Cardiology (N.M.M.P., J.W.J.) and Surgery (P.H.A.Q.),

Activation of Nuclear Receptor Nur77 by 6Mercaptopurine Protects Against Neointima Formation

2010

The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice

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...

Nuclear Receptors Nur77, Nurr1, and NOR-1 Expressed in Atherosclerotic Lesion Macrophages Reduce Lipid Loading and Inflammatory Responses

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.

Angiotensin II Type 1 Receptor Blockade Attenuates In-Stent Restenosis by Inhibiting Inflammation and Progenitor Cells

Hypertension, 2006

The precise mechanism by which angiotensin II type 1 receptor blocker reduces in-stent restenosis in clinical trials is unclear. We, therefore, investigated the mechanism of in-stent neointima formation. Male cynomolgus monkeys and rabbits were fed a high-cholesterol diet and were allocated to untreated control and type 1 receptor blocker groups. Five days after grouping, multilink stents were implanted in the iliac artery. The type 1 receptor blocker reduced the development of in-stent neointima formation by Ϸ30% in rabbits and monkeys. To investigate potential mechanisms, we examined the expression of renin-angiotensin system markers, all of which increased in monocytes and smooth muscle-like cells in the neointima and media within 7 days. The type 1 receptor blocker attenuated increased oxidative stress, the enhanced expression of markers of the rennin-angiotensin system and monocyte chemoattractant protein-1, and macrophage infiltration. The effects of type 1 receptor blocker on the differentiation of peripheral blood mononuclear cells into vascular progenitor cells were also examined. Treatment with type 1 receptor blocker suppressed the enhanced differentiation to smooth muscle progenitor cells induced by stenting. The type 1 receptor blocker attenuated in-stent neointima formation by inhibiting redox-sensitive inflammatory changes and by reducing recruitment of the progenitor cells. These potential actions of type 1 receptor blocker on inflammation and progenitor cells constitute a novel mechanism of suppression of in-stent restenosis by type 1 receptor blocker. (Hypertension. 2006;48:664-670.

GENES and In-Stent Restenosis: Review

International Journal of Research in Pharmaceutical Sciences

The initiation of coronary stents is a vast landmark in the practice of interventional cardiology. The vascular injury sustained during the percutaneous coronary intervention (PCI) leads to a complicated inflammatory and repairing process. Therefore, stent restenosis arises. Diabetes mellitus is the highest-risk clinical predictor of ISR. Genetics has an important role in the development of ISR. There is a suggested association between the appearance of stent restenosis and certain genetic polymorphisms. Examples of these single nucleotide polymorphisms are endothelial nitric oxide synthase gene (eNOS), the angiotensin converting enzyme gene (ACE), the angiotensin II type 1 receptor gene (AT1R), TGF-β, and VEGF. CYP2C19 variants can help change the medical strategy to a more individualized therapeutic regimen either by altering the therapeutic dose depending on the genotype or using an alternative drug that does not worsen the patient’s case. However, eNOS polymorphism produces gene...

Tumor necrosis factor- plays an important role in restenosis development

Faseb Journal, 2005

Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNF␣, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER) project included 3104 patients who underwent a successful PCI. Systematic genotyping for six polymorphisms in the TNF␣ gene was performed. The role of TNF␣ in restenosis was also assessed in ApoE*3-Leiden mice, TNF␣ knockout mice, and by local delivery of a TNF␣ biosynthesis inhibitor, thalidomide. The -238G-1031T haplotype of the TNF␣ gene increased clinical and angiographic risk of restenosis (P‫20.0؍‬ and P‫,200.0؍‬ respectively). In a mouse model of reactive stenosis, arterial TNF␣ mRNA was significantly time-dependently up-regulated. Mice lacking TNF␣ or treated locally with thalidomide showed a reduction in reactive stenosis (P‫10.0؍‬ and P‫,500.0؍‬ respectively). Clinical and preclinical data indicate that TNF␣ plays an important role in restenosis. Therefore, TNF␣ genotype may be used as a risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Inhibition of TNF␣ may be an anti-restenotic target strategy.-Monraats, P. S., Pires, N. M. M., Schepers, A., Agema, W. R. P., Boesten, L. S. M., de Vries, M. R., Zwinderman, A. H., de Maat, M. P. M., Doevendans, P. A. F. M., de Winter, R. J., Tio, R. A., Waltenberger, J., 't Hart, L. M., Frants, R. R., Quax, P. H. A., van Vlijmen, B. J. M., Havekes, L. M., van der Laarse, A., van der Wall, E. E., Jukema, J. W. Tumor necrosis factor-␣ plays an important role in restenosis development. 1998 0892-6638/05/0019-1998 © FASEB BMI: body mass index; MI: myocardial infarction; LAD: left anterior descending branch of the left coronary artery; RCX: circumflex branch of the left coronary artery; MI: myocardial infarction; CABG: coronary artery bypass grafting. Age is mean Ϯ SD; other variables are percentage of patients. *P-value determined by Cox regression analysis.

Pathogen burden, inflammation, proliferation and apoptosis in human in-stent restenosis

Journal of vascular …, 2004

Pathogenic events leading to in-stent restenosis (ISR) are still incompletely understood. Among others, inflammation, immune reactions, deregulated cell death and growth have been suggested. Therefore, atherectomy probes from 21 patients with symptomatic ISR were analyzed by immunohistochemistry for pathogen burden and compared to primary target lesions from 20 stable angina patients. While cytomegalovirus, herpes simplex virus, Epstein-Barr virus and Helicobacter pylori were not found in ISR, acute and/or persistent chlamydial infection were present in 6/21 of these lesions (29%). Expression of human heat shock protein 60 was found in 8/21 of probes (38%). Indicated by distinct signals of CD68, CD40 and CRP, inflammation was present in 5/21 (24%), 3/21 (14%) and 2/21 (10%) of ISR cases. Cell density of ISR was significantly higher than that of primary lesions (977 B 315 vs. 431 B 148 cells/mm 2 ; p ! 0.001). There was no replicating cell as shown by Ki67 or PCNA. TUNEL + cells indicating apoptosis were seen in 6/21 of ISR specimens (29%). Quantitative analysis revealed lower expression levels for each intimal determinant in ISR compared to primary atheroma (all p ! 0.05). In summary, human ISR at the time of clinical presentation is characterized by low frequency of pathogen burden and inflammation, but pronounced hypercellularity, low apoptosis and absence of proliferation.

Inflammation as a mechanism and therapeutic target for in-stent restenosis

Current atherosclerosis reports, 2005

Restenosis following coronary stenting has long been attributed to neointimal proliferation, thrombosis, and negative remodeling. More recently, the important role of inflammation in vascular healing has also been increasingly well understood. From animal models and from clinical experience, we know that endothelial injury, platelet and leukocyte interactions, and subcellular chemoattractant and inflammatory mediators are pivotal in the development of the inflammatory response following stent implantation. By examining the specific mechanisms governing the inflammatory response to percutaneous coronary intervention, we may gain insight into potential therapeutic targets and strategies to prevent restenosis in clinical practice.

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 (original) (raw)

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