6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

Yg, Yoo; Ty, Na; Wk, Yang; Kim, Hyung Jun; Ik, Lee; Kong, Gu; Jh, Chung; Mo, Lee

doi:10.1038/sj.onc.1210149

Cited by 40 publications

(52 citation statements)

References 58 publications

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“…5,7 Likewise, effects of 6-MP on endothelial cells are described, including effects of 6-MP on purine synthesis, 20 but also enhancement of HIF1␣ activity and angiogenesis partly mediated through activation of Nur77 by 6-MP. 21 It will be extremely relevant to study 6-MP in these other vascular cells with respect to atherosclerosis and under inflammatory conditions to gain even further insight into effects of 6-MP on atherosclerosis. We have previously demonstrated that Nur77 is crucially involved in the inhibition of proliferation of venous SMCs by 6-MP.…”

Section: Pols Et Al 6-mercaptopurine In Atherosclerosismentioning

confidence: 99%

6-Mercaptopurine Inhibits Atherosclerosis in Apolipoprotein E*3-Leiden Transgenic Mice Through Atheroprotective Actions on Monocytes and Macrophages

Pols

Bonta

Pires

et al. 2010

ATVB

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Objective-6-Mercaptopurine (6-MP), the active metabolite of the immunosuppressive prodrug azathioprine, is commonly used in autoimmune diseases and transplant recipients, who are at high risk for cardiovascular disease. Here, we aimed to gain knowledge on the action of 6-MP in atherosclerosis, with a focus on monocytes and macrophages. Methods and Results-We demonstrate that 6-MP induces apoptosis of THP-1 monocytes, involving decreased expression of the intrinsic antiapoptotic factors B-cell CLL/Lymphoma-2 (Bcl-2) and Bcl2-like 1 (Bcl-x L ). In addition, we show that 6-MP decreases expression of the monocyte adhesion molecules platelet endothelial adhesion molecule-1 (PECAM-1) and very late antigen-4 (VLA-4) and inhibits monocyte adhesion. Screening of a panel of cytokines relevant to atherosclerosis revealed that 6-MP robustly inhibits monocyte chemoattractant chemokine-1 (MCP-1) expression in macrophages stimulated with lipopolysaccharide (LPS). Finally, local delivery of 6-MP to the vessel wall, using a drug-eluting cuff, attenuates atherosclerosis in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice (PϽ0.05). In line with our in vitro data, this inhibition of atherosclerosis by 6-MP was accompanied with decreased lesion monocyte chemoattractant chemokine-1 levels, enhanced vascular apoptosis, and reduced macrophage content. Conclusion-We

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Section: Pols Et Al 6-mercaptopurine In Atherosclerosismentioning

confidence: 99%

6-Mercaptopurine Inhibits Atherosclerosis in Apolipoprotein E*3-Leiden Transgenic Mice Through Atheroprotective Actions on Monocytes and Macrophages

Pols

Bonta

Pires

et al. 2010

ATVB

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“…The HRE-tk-Luc, VEGF promoter (Ϫ2068 to ϩ50)-Luc, and Gal4-tk-Luc reporter constructs have been described previously. 8,27,29 The eukaryotic expression vectors such as pEGFP-C3-HIF-1␣ (GFP-HIF-1␣), p3XFLAG TM 7.1-FLAG-HIF-1␣, VP16-HIF-1␣, and glutathione S-transferase (GST)-fused HIF-1␣ (pEBG-HIF-1␣) and truncated constructs were described previously. 27,29 The Gal4 DBD-fused ROR␣1, FLAG-tagged full-length and truncated ROR␣1 constructs, HA-tagged ROR␣4, and antisense (AS)-ROR␣1 plasmids were constructed by conventional rDNA technology.…”

Section: Plasmids and Transient Transfectionmentioning

confidence: 99%

“…27,29 Immunoprecipitation and subcellular fractionation was carried out basically as described previously. 27,28 …”

Section: Western Blotting Immunoprecipitation and Subcellular Fractmentioning

confidence: 99%

“…We have previously shown that the Nur77 family of orphan nuclear receptors and their activators stabilize and transactivate HIF-1␣. 28,29 Recently, it was reported that ROR␣ expression is upregulated in several types of cells, including human SMCs and ECs, under hypoxia or in the presence of inflammatory cytokines such as IL-1␤ and TNF␣. 18,30,31 The potential implication of ROR␣ in the hypoxia signaling pathway prompted us to study its role in transcriptional activation of HIF-1␣.…”

mentioning

confidence: 99%

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Transcriptional Activation of HIF-1 by RORα and its Role in Hypoxia Signaling

Kim

Yoo

Yang

et al. 2008

ATVB

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Objective-Hypoxia-inducible factor 1␣ (HIF-1␣) is primarily involved in the adapting of cells to changes in oxygen levels, which is essential for normal vascular function. Recently, physiological roles for retinoic acid-related orphan receptor ␣ (ROR␣) have been implicated in cardiovascular diseases such as atherosclerosis. In this study, we have investigated the potential roles of ROR␣ in the hypoxia signaling pathway in connection with activation of HIF-1␣. Key Words: ROR␣ Ⅲ hypoxia Ⅲ HIF-1␣ Ⅲ melatonin Ⅲ vascular endothelial growth factor R etinoic acid receptor-related orphan receptor ␣ (ROR␣; NR1F1) is a member of the steroid/thyroid hormone receptor superfamily of transcriptional factors and is closely related to the retinoic acid receptors. 1,2 ROR␣ exists in 4 isoforms, ROR␣1, ROR␣2, ROR␣3, and ROR␣4 (also known as RZR␣), which are generated by a combination of alternative promoter use and exon splicing of the RORA gene. 2 These isoforms comprise a common DNA-binding domain (DBD) and a putative ligand-binding domain (LBD), but differ by their N-terminal sequences. 3 Melatonin and synthetic thiazolidine diones have been shown to transactivate ROR␣, although these observations need to be clarified. 4,5 Recently, analysis of the crystal structure of the ligand-binding domain of ROR␣ revealed that a ligand is present in the binding pocket. This was identified as cholesterol, suggesting that plasma and intracellular levels of cholesterol may be important in the regulation of transcriptional activity for ROR␣. 6,7 ROR␣ usually binds as a monomer to a ROR response element (RORE) consisting of a half site core AGGTCA motif or as a homodimer to a direct repeat of the core motif separated by 2 base pairs. 1 Putative ROREs have been identified in the promoters, such as human fibrinogen ␤, Apo A-V, Apo A-I, Apo C-III, PPAR␥, and RevErb␣, which may suggest a role of this receptor in lipid metabolism and cardiovascular physiology. 8 -12 However, little is known regarding the internal and external stimuli that regulate the RORA gene expression.ROR␣ functions have been studied with the help of the staggerer (sg/sg) mutant mouse. A spontaneous mutation in the ligand-binding domain induces a frameshift that results in a protein truncated in its C terminus and generates the staggerer phenotype. 13 These animals experience severe cerebellar ataxia caused by massive neurodegeneration of Purkinje cells. 14 Moreover, the phenotype of these mice revealed that ROR␣ is crucially involved in regulating the inflammatory and immune responses and lipid metabolism, which are closely related to vascular disorders such as atherosclerosis. 15,16 In the staggerer mice, angiogenesis is enhanced markedly after ischemia induced by the ligation of the femoral artery. 17 In the vascular system, ROR␣ mRNAs have been detected in human smooth muscle cells (SMCs), endothelial cells (ECs), as well as mammary arteries. 16,18 ROR␣ expression level is significantly decreased in human atherosclerotic plaques, whereas increased expression is observed a...

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“…Azathioprine (Aza) caught our attention because of its described beneficial effects on endothelial cells (ECs). Aza increases EC survival, 17 in contrast to sirolimus, which induces apoptosis, causing the thrombotic problems in sirolimus-coated coronary stents, 18 or cyclosporine A that is toxic to ECs and provokes vasculopathy. 19 We and others have previously shown that Aza maintains the contractile phenotype of smooth muscle cells 20,21 and has an anti-inflammatory effect in macrophages 22 and T cells.…”

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confidence: 99%

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

Marinković

Hibender

Hoogenboezem

et al. 2013

ATVB

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Objective— In aortic aneurysms the arterial vessel wall is dilated because of destruction of its integrity, which may lead to lethal vessel rupture. Chronic infiltration of inflammatory cells into the vessel wall is fundamental to aneurysm pathology. We aim to limit aneurysm growth by inhibition of inflammation and reducing endothelial cell (EC) activation with immunosuppressive drug azathioprine (Aza). Approach and Results— Aza and its metabolite 6-mercaptopurine have anti-inflammatory effects on leukocytes. We here demonstrate that treatment of ECs with 6-mercaptopurine inhibits cell activation as illustrated by reduced expression of interleukin-12, CCL5, CCL2, and vascular cell adhesion molecule-1 and inhibition of monocyte–EC adhesion. The underlying mechanism of 6-mercaptopurine involves suppression of GTPase Rac1 activation, resulting in reduced phosphorylation of c-Jun-terminal-N-kinase and c-Jun. Subsequently, the effect of Aza was investigated in aneurysm formation in the angiotensin II aneurysm mouse model in apolipoprotein E–deficient mice. We demonstrated that Aza decreases de novo aortic aneurysm formation from an average aneurysm severity score of 2.1 (control group) to 0.6 (Aza group), and that Aza effectively delays aorta pathology in a progression experiment, resulting in a reduced severity score from 2.8 to 1.7 in Aza-treated mice. In line with the in vitro observations, Aza-treated mice showed less c-Jun-terminal-N-kinase activation in ECs and reduced leukocyte influx in the aortic wall. Conclusions— The immunosuppressive drug Aza has an anti-inflammatory effect and in ECs inhibits Rac1 and c-Jun-terminal-N-kinase activation, which may explain the protective effect of Aza in aneurysm development and, most importantly for clinical implications, aneurysm severity.

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6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1α resulting in new vessel formation

Cited by 40 publications

References 58 publications

6-Mercaptopurine Inhibits Atherosclerosis in Apolipoprotein E*3-Leiden Transgenic Mice Through Atheroprotective Actions on Monocytes and Macrophages

6-Mercaptopurine Inhibits Atherosclerosis in Apolipoprotein E*3-Leiden Transgenic Mice Through Atheroprotective Actions on Monocytes and Macrophages

Transcriptional Activation of HIF-1 by RORα and its Role in Hypoxia Signaling

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

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