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

Kumar, Alan Prem; Piedrafita, F. Javier; Reynolds, Wanda F.

doi:10.1074/jbc.m311625200

Cited by 98 publications

(116 citation statements)

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“…Elevated serum MPO is an indicator for heightened risk of coronary artery disease (CAD) events [19,20], while individuals with inherited MPO deficiencies have reduced cardiovascular disease [21]. Members of the nuclear receptor superfamily, notably PPARγ and estrogen receptor, have been found to play key roles in regulating human MPO gene expression [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…A functional MPO promoter polymorphism, −463 G/A, alters expression levels [12,13], and is associated with increased incidence of CAD [14][15][16] and severity of atherosclerosis [17,18]. Elevated serum MPO is an indicator for heightened risk of coronary artery disease (CAD) events [19,20], while individuals with inherited MPO deficiencies have reduced cardiovascular disease [21].…”

Section: Introductionmentioning

confidence: 99%

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The human myeloperoxidase gene is regulated by LXR and PPARα ligands

Reynolds

Kumar

Piedrafita

2006

Biochemical and Biophysical Research Communications

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Myeloperoxidase (MPO) is an oxidant-generating enzyme expressed in macrophages and implicated in atherosclerosis and cholesterol homeostasis. LXRα and PPARα regulate genes involved in cholesterol metabolism and the inflammatory response in macrophages. Here we examine the effect of LXR and PPARα ligands on MPO expression. LXR and PPARα, as heterodimers with RXR, are shown to bind overlapping sites in an Alu receptor response element (AluRRE) in the MPO promoter. The LXR ligand T0901317 suppresses MPO mRNA expression in primary human macrophages, and in bone marrow cells and macrophages from huMPO transgenic mice. The PPARα ligand GW9578 downregulates MPO expression in GMCSF-macrophages, while upregulating in MCSFmacrophages. In contrast, the mouse MPO gene, which lacks the primate-specific AluRRE, is not regulated by LXR or PPARα ligands. These findings identify human MPO as a novel LXR and PPARα target gene, consistent with the role of these receptors in regulation of proinflammatory genes in macrophages.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The human myeloperoxidase gene is regulated by LXR and PPARα ligands

Reynolds

Kumar

Piedrafita

2006

Biochemical and Biophysical Research Communications

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“…This cluster is recognized by various nuclear receptors (Piedrafita et al 1996;Vansant and Reynolds 1995): c.-653G in the first hexamer creates an SP1 site, whereas c.-653A creates a binding site for the estrogen receptor a (ER-a). This raises the possibility that the estrogen receptor may contribute to differential regulation of MPO among G and A allele carriers in men and women, as reported in numerous studies (Kumar et al 2004;Reynolds et al 2000;Norris et al 1995). In this regard, we analyzed the effects of the MPO c.-653G [ A polymorphism on LDL characteristics separately in men and women.…”

Section: Discussionmentioning

confidence: 99%

“…However, Kumar et al (Kumar et al 2004) demonstrated that gender differences in MPO c.-653G [ A polymorphism association are not caused by a direct impact of estrogen receptor binding on the MPO promoter. Indeed, PPARG heterodimerizes with retinoid X receptor (RXR) to bind two direct MPO hexamers.…”

Section: Discussionmentioning

confidence: 99%

“…We also hypothesize that polymorphisms in the peroxisome proliferator-activated receptor c (PPARG) gene, such as the P12A (Yen et al 1997), exacerbate the effects of MPO gene polymorphisms on LDL characteristics. This is based on the fact that PPARG ligands have been shown to regulate MPO gene expression (Kumar et al 2004). Thus, the objectives of our study were first to identify MPO gene sequence variations and to test the associations between these MPO gene polymorphisms and LDL features.…”

Section: Introductionmentioning

confidence: 99%

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Myeloperoxidase gene sequence variations are associated with low-density-lipoprotein characteristics

et al. 2008

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The small, dense low-density-lipoprotein (LDL) phenotype is associated with an increased atherosclerosis risk. A genome-wide scan performed on 236 nuclear families of the Quebec Family Study (QFS) revealed a quantitative trait locus (QTL) for LDL peak-particle size (LDL-PPD) on the 17q21 region. This region encodes the myeloperoxidase (MPO) gene. MPO is able to oxidize LDL by its reactive intermediates. To test the associations between MPO gene polymorphisms and LDL-PPD as well as plasma lipid levels, we performed direct sequencing of the coding regions, exon-intron splicing boundaries, and the regulatory regions on 25 subjects to identify new genetic variants. Genotyping was performed either by TaqMan or direct sequencing on 680 subjects in the QFS. LDL-PPD was measured by gradient gel electrophoresis (GGE) on nondenaturing 2-16% polyacrylamide gradient gels. MPO gene sequencing revealed 16 polymorphisms. The c.-653G [ A MPO polymorphism was associated with lower plasma total cholesterol, LDL cholesterol (LDL-C), and LDL apolipoprotein B (LDL-apoB) levels (P = 0.026, 0.042 and 0.014, respectively). No significant association with a gene-dosage effect were observed for LDL-PPD. The MPO gene variants are not associated with LDL-PPD and thus are unlikely to be responsible for the quantitative trait locus reported on 17q21. However, the c.-653G [ A is associated with plasma LDL-C and LDL-apoB concentrations.

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Myeloperoxidase Controls Bone Turnover by Suppressing Osteoclast Differentiation Through Modulating Reactive Oxygen Species Level

Zhao

Lin

et al. 2020

Journal of Bone and Mineral Research

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Myeloperoxidase (MPO) is a heme peroxidase that plays an important role in innate immunity for host defense against invading microorganisms by catalyzing hydrogen peroxide (H2O2)‐mediated reactions. Although many reports indicate MPO exerts beneficial or detrimental effects on a variety of inflammatory diseases, little is known with regard to its functional role in bone homeostasis in vivo. Here, our work demonstrates that MPO was transcriptionally downregulated in response to osteoclastogenic stimuli and that exogenous alteration of MPO expression negatively regulated osteoclast (OC) differentiation in vitro. Genetic ablation of Mpo resulted in osteoporotic phenotypes and potentiated bone‐resorptive capacity in mice. Mechanistically, accumulation of intracellular H2O2 and reactive oxygen species (ROS) were observed in MPO deficiency, and MPO overexpression suppressed ROS production in mouse OC precursors. Moreover, a ROS scavenger Tempol inhibited the effect of MPO deficiency on OC formation and function as well as on receptor activator of nuclear factor‐κB ligand (RANKL)‐initiated transduction signal activation including NF‐κB, mitogen‐activated protein kinases (MAPKs), and Akt, indicating the increased ROS caused by MPO deficiency contributes to osteoclastogenesis. Taken together, our data demonstrate that MPO has a protective role in bone turnover by limiting osteoclastogenesis and bone resorption physiologically through modulating intracellular H2O2 level. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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

Cited by 98 publications

References 68 publications

The human myeloperoxidase gene is regulated by LXR and PPARα ligands

The human myeloperoxidase gene is regulated by LXR and PPARα ligands

Myeloperoxidase gene sequence variations are associated with low-density-lipoprotein characteristics

Myeloperoxidase Controls Bone Turnover by Suppressing Osteoclast Differentiation Through Modulating Reactive Oxygen Species Level

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