Roles of Xenobiotic Receptors in Vascular Pathophysiology

Xiao, Lei; Zhang, Zihui; Luo, Xiaoqin

doi:10.1253/circj.cj-14-0343

Cited by 31 publications

(34 citation statements)

References 138 publications

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“…The activation of these enzymes results in AhR ligands inducing their own metabolism and clearance from the body (Beischlag et al 2008). This, combined with the fact that AhR is a relatively ubiquitous protein that is expressed in most bodily tissues, has resulted in AhR being recognized as the body's primary molecular defense when presented with an environmental toxin (Xiao et al 2014). …”

Section: Potential Mechanisms Of Pcb-induced Cardiovascular Diseasementioning

confidence: 99%

“…Previous work has demonstrated that coplanar PCBs are capable of acting as AhR agonists (Han et al 2012, Hennig et al 2002, Lim et al 2008, Xiao et al 2014). The toxicity that is then caused by these coplanar PCBs while stimulating AhR is often attributed to the release of reactive oxygen species (ROS) and the subsequent increase in oxidative stress (Schlezinger et al 2006).…”

Section: Potential Mechanisms Of Pcb-induced Cardiovascular Diseasementioning

confidence: 99%

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Polychlorinated biphenyls and links to cardiovascular disease

Perkins

Petriello

Newsome

et al. 2015

Environ Sci Pollut Res

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The pathology of cardiovascular disease is multi-faceted, with links to many modifiable and non-modifiable risk factors. Epidemiological evidence now implicates exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), with an increased risk of developing diabetes, hypertension, and obesity; all of which are clinically relevant to the onset and progression of cardiovascular disease. PCBs exert their cardiovascular toxicity either directly or indirectly via multiple mechanisms, which are highly dependent on the type and concentration of PCBs present. However, many PCBs may modulate cellular signaling pathways leading to common detrimental outcomes including induction of chronic oxidative stress, inflammation, and endocrine disruption. With the abundance of potential toxic pollutants increasing globally, it is critical to identify sensible means of decreasing associated disease risks. Emerging evidence now implicates a protective role of lifestyle modifications such as increased exercise and/or nutritional modulation via anti-inflammatory foods, which may help to decrease the vascular toxicity of PCBs. This review will outline the current state of knowledge linking coplanar and non-coplanar PCBs to cardiovascular disease and describe the possible molecular mechanism of this association.

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Section: Potential Mechanisms Of Pcb-induced Cardiovascular Diseasementioning

confidence: 99%

Section: Potential Mechanisms Of Pcb-induced Cardiovascular Diseasementioning

confidence: 99%

Polychlorinated biphenyls and links to cardiovascular disease

Perkins

Petriello

Newsome

et al. 2015

Environ Sci Pollut Res

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“…PXR is also involved in atherosclerosis development and vascular functions, to mention only a few more of its activities beyond the xenobiotic-sensing function (Febbraio et al, 2000;Masuyama et al, 2000;Takeshita et al, 2001;Zhou et al, 2006b;Guy et al, 2007;Newbold et al, 2007;vom Saal and Myers, 2008;Carwile and Michels, 2011). These aforementioned functions of PXR have been reviewed in great detail (Konno et al, 2008;Wada et al, 2009;Xiao et al, 2014); thus, it will not be discussed in this review. The discoveries of hitherto unsuspected roles for PXR have ignited a new appreciation for the receptor and suggest that PXR signaling may contribute more substantially to pathophysiologic conditions than we currently understand.…”

Section: Introductionmentioning

confidence: 99%

PXR: More Than Just a Master Xenobiotic Receptor

2017

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Pregnane X receptor (PXR) is a nuclear receptor considered to be a master xenobiotic receptor that coordinately regulates the expression of genes encoding drug-metabolizing enzymes and drug transporters to essentially detoxify and eliminate xenobiotics and endotoxins from the body. In the past several years, the function of PXR in the regulation of xenobiotic metabolism has been extensively studied, and the role of PXR as a xenobiotic sensor has been well established. It is now clear, however, that PXR plays many other roles in addition to its xenobiotic-sensing function. For instance, recent studies have discovered previously unidentified roles of PXR in inflammatory response, cell proliferation, and cell migration. PXR also contributes to the dysregulation of these processes in diseases states. These recent discoveries of the role of PXR in the physiologic and pathophysiologic conditions of other cellular processes provides the possibility of novel targets for drug discovery. This review highlights areas of PXR regulation that require further clarification and summarizes the recent progress in our understanding of the nonxenobiotic functions of PXR that can be explored for relevant therapeutic applications.

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“…The activation of these enzymes results in AhR ligands inducing their own metabolism and clearance from the body[21]. Previous work has demonstrated that coplanar PCBs are capable of acting as AhR agonists [20, 22, 23]. The toxicity that is then caused by coplanar PCBs while stimulating AhR and coupled with induction of P450 enzymes is often attributed to the release of reactive oxygen species (ROS) and a subsequent increase in oxidative stress [24].…”

Section: Introductionmentioning

confidence: 99%

Dioxin-like pollutants increase hepatic flavin containing monooxygenase (FMO3) expression to promote synthesis of the pro-atherogenic nutrient biomarker trimethylamine N-oxide from dietary precursors

Petriello

Hoffman

Sunkara

et al. 2016

The Journal of Nutritional Biochemistry

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The etiology of cardiovascular disease (CVD) is impacted by multiple modifiable and non-modifiable risk factors including dietary choices, genetic predisposition, and environmental exposures. However, mechanisms linking diet, exposure to pollutants, and CVD risk are largely unclear. Recent studies identified a strong link between plasma levels of nutrient-derived Trimethylamine N-oxide (TMAO) and coronary artery disease. Dietary precursors of TMAO include carnitine and phosphatidylcholine, which are abundant in animal-derived foods. Dioxin-like pollutants can upregulate a critical enzyme responsible for TMAO formation, hepatic flavin containing monooxygenase 3 (FMO3), but a link between dioxin-like PCBs, upregulation of FMO3, and increased TMAO has not been reported. Here, we show that mice exposed acutely to dioxin-like PCBs exhibit increased hepatic FMO3 mRNA, protein, as well as an increase in circulating levels of TMAO following oral administration of its metabolic precursors. C57BL/6 mice were exposed to 5 μmol PCB 126/kg mouse weight (1.63 mg/kg). At 48 h post-PCB exposure, mice were subsequently given a single gavage of phosphatidylcholine dissolved in corn oil. Exposure to 5 μmole/kg PCB 126 resulted in greater than 100-fold increase in FMO3 mRNA expression, robust induction of FMO3 protein, and a 5-fold increase in TMAO levels compared with vehicle treated mice. We made similar observations in mice exposed to PCB 77 (49.6 mg/kg twice); stable isotope tracer studies revealed increased formation of plasma TMAO from an orally administered precursor trimethylamine (TMA). Taken together, these observations suggest a novel diet-toxicant interaction that results in increased production of a circulating biomarker of cardiovascular disease risk.

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Roles of Xenobiotic Receptors in Vascular Pathophysiology

Cited by 31 publications

References 138 publications

Polychlorinated biphenyls and links to cardiovascular disease

Polychlorinated biphenyls and links to cardiovascular disease

PXR: More Than Just a Master Xenobiotic Receptor

Dioxin-like pollutants increase hepatic flavin containing monooxygenase (FMO3) expression to promote synthesis of the pro-atherogenic nutrient biomarker trimethylamine N-oxide from dietary precursors

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