Molecular analysis of the human myeloperoxidase promoter region.

Chumakov, Alexey M.; Chumakova, E. A.; Chih, Doris Y.; Koeffler, H. Phillip

doi:10.3892/ijo.16.2.401

Cited by 8 publications

(12 citation statements)

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“…-463G/A polymorphism at one of the upstream Alu MPO promoter elements has been linked to increased incidence of coronary artery disease in the general population (69,70) and CVD incidence in CKD patients (71) and ESRD patients (72). This primate-specific promoter contains binding site for nuclear transcription factors, namely SP1-thyroid hormone-retinoic acid response element (73), peroxisome proliferator activated receptor alpha and gamma, retinoid X receptors (74), statins (75), and the liver X receptor (76), which promote MPO expression and is competitively inhibited by the estrogen (68). This promotor is absent in mice, a finding that may partially explain the marked absence of MPO or MPO activity in the mouse model and the failure of MPO-deficient mice to ameliorate atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

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Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptordeficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products, and the protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and o,o′-dityrosine were examined with immunoassays and confirmed with mass spectrometry (MS). As anticipated, the CKD mice had significantly higher plasma creatinine, urea nitrogen, and intact parathyroid hormone along with lower hematocrit and body weight. On both the diet regimens, CKD mice did not have hypertension but had lower cholesterol and triglyceride levels than the control mice. Despite the lower cholesterol levels, CKD mice had increased aortic plaque areas, fibrosis, and luminal narrowing. They also exhibited increased MPO expression and activity (i.e., increased oxidized tyrosines) that co-localized with infiltrating lesional macrophages and diminished vascular reactivity. In summary, unlike non-CKD mouse models of atherosclerosis, CKD mice exhibit increased MPO expression and catalytic activity in atherosclerotic lesions, which colocalize with lesional macrophages. These results implicate macrophage-derived MPO in CKDaccelerated atherosclerosis.Chronic kidney disease (CKD) affects 15% of Americans, and cardiovascular disease (CVD) continues to be the leading cause of mortality in Myeloperoxidase oxidizes artery proteins in kidney disease2 these patients (>10-fold mortality compared to the general population) (1-6). An increased risk for CVD is evident even in milder and non-albuminuric forms of CKD and cannot be fully explained by traditional risk factors (7-10). Furthermore, control of established risk factors such as hyperlipidemia results in substantially lower risk reduction in CKD patients compared to the general population (11). Recent evidence supports the key role of nontraditional risk factors (e.g., oxidative stress) in the pathogenesis of CVD in CKD (12-17), suggesting that CKD-specific mechanisms are responsible for CVD in kidney patients.Atherosclerosis, the major cause of CVD, is a chronic inflammatory disease characterized by the infiltration of lipids and inflammatory cells, such as monocyte-derived macrophages and Tlymphocytes, into the artery wall (18). While elevated levels of low-density lipoprotein (LDL) are known to increase the risk of atherosclerosis greatly (19), in vitro studies sugges...

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Section: Discussionmentioning

confidence: 99%

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

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“…Chloramphenicol acetyl transferase (CAT) assays were performed using a composite ATF4/CEBP-⑀ binding site dimer cloned into the pCATB reporter plasmid as described previously. 13,18 Mouse 32Dcl3 cells were grown in RPMI1640 medium supplemented with 10% fetal calf serum and 10% of WEHI3B cell-conditioned medium as a source of IL-3. To induce neutrophil differentiation, cells were plated in medium without IL-3, supplemented with 100 ng/mL G-CSF.…”

Section: Transient Transfections and Reporter Assaysmentioning

confidence: 99%

Modulation of DNA binding properties of CCAAT/enhancer binding protein epsilon by heterodimer formation and interactions with NFkappaB pathway

Chumakov

Silla

Williamson

et al. 2007

Blood

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IntroductionSpecific regulation of gene expression is achieved through interaction of multiple transcriptional activators and repressors with their cognate DNA sites. This activity is subject to several levels of control, including posttranslational modification by phosphorylation, acetylation, selective degradation, and interaction with coactivators and corepressors.Previous studies of CCAAT/enhancer binding protein family of transcriptional activators had identified domains responsible for dimerization, specific DNA recognition, transcriptional activation, and intramolecular repression. [1][2][3][4][5][6] Several members of the C/EBP protein family (C/EBP-␣, C/EBP-␤, C/EBP-␦, C/EBP-⑀) contain a transactivation domain and a basic "leucine zipper" domain that serve for DNA recognition and dimer formation. Others like C/EBP-␥ and C/EBP-(CHOP, GADD153) are involved in transcriptional regulation through dimerization with other basic leucine zipper proteins from the C/EBP, ATF/CREB, and Fos/Jun families.Recent studies directed at identification of C/EBP-responsive genes resulted in identification of a diverse and degenerate collection of putative C/EBP binding sites. At the same time, in vitro experiments with site selection typically produce very common short consensus sequences. Identification of binding sites for each individual member of the C/EBP family is complicated by common coexpression of several of these proteins in the same cell and their ability to form heterodimeric complexes with each other and with structurally related ATF/CREB proteins. [7][8][9][10][11][12] Activity of C/EBP proteins is regulated by phosphorylation mediated through several major kinase pathways that affect DNA binding, subcellular localization in the nucleus, and interaction with cell-cycle proteins. Our recent studies of C/EBP-⑀ phosphorylation 13,14 identified several sites, including 1 for p38 MAPK within the transactivation domain of C/EBP-⑀. As a result of phosphorylation at threonine 75 (T75), C/EBP-⑀ DNA binding and specific transcriptional activity was significantly enhanced.In this study, we identified consensus binding sequences for C/EBP-⑀ and for heterodimers of C/EBP-⑀ with its most common dimerization partner ATF4. 15,16 Furthermore, we find that C/EBP-⑀-DNA interaction is highly up-regulated by interaction with the activated NFkappaB pathway protein p65RelA. This interaction depends on the T75 phosphorylation status of C/EBP-⑀ and can be enhanced by introduction of phosphomimetic Thr to Asp mutation. By using selective removal of p65RelA-and siRNA-mediated p65 knock-down, we demonstrate that the activated NFkappaB pathway is required for high-level expression of the C/EBP-⑀-responsive promoter. This novel interaction may play an important role in regulation of C/EBP-⑀-dependent genes in myeloid cells. Materials and methodsCMV-C/EBP-⑀, ATF4, and siRNA expression constructs C/EBP-⑀, C/EBP-⑀T75A, and C/EBP-⑀T75D expression and pMimluciferase reporter plasmids were described previously. 6,13,14 ATF4 (CREB2) expression pl...

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“…The promoter elements that regulate the myeloid-specific expression of the MPO gene are only partially understood (34). A functional upstream promoter polymorphism, Ϫ463GA, has been associated with expression levels (35,36), as well as incidence or severity of atherosclerosis (13,14), Alzheimer's (20, 38 -40), MPO-anti-neutrophil cytoplasmic antibodies vasculitis (41), hepatitis C virus-induced fibrosis (42), multiple sclerosis (43), periodontal disease (44), lung cancer (44,46), and myeloid leukemia (35).…”

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confidence: 99%

Peroxisome Proliferator-activated Receptor γ Ligands Regulate Myeloperoxidase Expression in Macrophages by an Estrogen-dependent Mechanism Involving the -463GA Promoter Polymorphism

Kumar

Piedrafita

Reynolds

2004

Journal of Biological Chemistry

105

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A functional myeloperoxidase (MPO) promoter polymorphism, ؊463GA, has been associated with incidence or severity of inflammatory diseases, including atherosclerosis and Alzheimer's disease, and some cancers. The polymorphism is within an Alu element encoding four hexamer repeats recognized by nuclear receptors (AluRRE). Here we show that peroxisome proliferatoractivated receptor ␥ (PPAR␥) agonists strongly regulate MPO gene expression through the AluRRE. Opposite effects were observed in granulocyte/macrophage colony-stimulating factor (GMCSF)-versus macrophage colony-stimulating factor (

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Molecular analysis of the human myeloperoxidase promoter region.

Cited by 8 publications

References 0 publications

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Modulation of DNA binding properties of CCAAT/enhancer binding protein epsilon by heterodimer formation and interactions with NFkappaB pathway

Peroxisome Proliferator-activated Receptor γ Ligands Regulate Myeloperoxidase Expression in Macrophages by an Estrogen-dependent Mechanism Involving the -463GA Promoter Polymorphism

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