Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl hydrocarbon receptor–tissue factor axis

Belghasem, Mostafa; Röth, Daniel; Richards, Sean; Napolene, Marc Arthur; Walker, Joshua; Yin, Wenqing; Arinze, Nkiruka; Lyle, Chimera; Spencer, Carolyn T.; Francis, Jean; Thompson, Cristal Reyna; Andry, Christopher D.; Whelan, Stephen A.; Lee, Norman; Ravid, Katya; Chitalia, Vipul C.

doi:10.1182/blood.2019001675

Cited by 33 publications

(23 citation statements)

References 61 publications

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“…Similar evidence of thrombus formation was reported after chronic oral exposure to IS in rat model [62] and in the mice models with higher IS doses (more than 30 mg/kg) [63]. Recently, in a model of cancer-associated thrombosis, increased levels of IS were observed and associated with more extensive thrombosis [64] extending the endotheliotoxic role of IS beyond uremia.…”

Section: Evidence For a Prothrombotic Statesupporting

confidence: 70%

“…IS activates the AhR genomic pathway with AhR nuclear translocation [91] and the AhR inflammatory non genomic pathway [92]. In vitro inactivation or pharmacological inhibition of the AhR in endothelial cells reverses tissue factor induction by IS [90,91] and similarly in vivo in mice [64]. Other aspects of endothelial dysfunction induced by IS were related to AhR activation.…”

Section: Indoxyl Sulfate a Uremic Endotheliotoxin: Aryl Hydrocarbon mentioning

confidence: 99%

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Indoxyl Sulfate, a Uremic Endotheliotoxin

Lano

Burtey

Sallée

2020

Toxins

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Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)—derived from tryptophan metabolism—accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients.

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Section: Evidence For a Prothrombotic Statesupporting

confidence: 70%

Section: Indoxyl Sulfate a Uremic Endotheliotoxin: Aryl Hydrocarbon mentioning

confidence: 99%

Indoxyl Sulfate, a Uremic Endotheliotoxin

Lano

Burtey

Sallée

2020

Toxins

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“…Plasma levels of the AhR agonists kynurenine and indoxyl sulfate increased in mice bearing cancer cell xenografts. This was accompanied by upregulation of TF and PAI-1 and increased clot weights in a venous thrombosis model of colon cancer [ 81 ]. The AhR antagonist CH223191 ameliorated these responses, suggesting a role for the endogenous tryptophan metabolites as enhancers of venous thrombogenicity [ 81 ].…”

Section: Ahr Expression/function In Pathophysiologymentioning

confidence: 99%

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Safe

Jin

Park

et al. 2020

IJMS

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The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors.

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“…After ACE2 mediated cell entry, coronaviruses firstly activate aryl hydrocarbon receptors (AhRs) without indoleamine 2,3dioxygenase (IDO1) stimulation (141). Activated AhRs initiates the production of inflammation factors (IL-1β, IL-6, and TNF-α), induces tissue factor (TF) and PAI-1 mediated thromboembolism (AhR-TF/PAI-1 pathway) (142), and lead multiple organ fibrosis via Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1)/IL-22 signaling pathway with signal transducer and activator of transcription 3 (STAT3) (143). The produced inflammatory cytokines trigger IDO1 that metabolizes tryptophan to kynurenine (AhR stimulator).…”

Section: Vitamin Ementioning

confidence: 99%

Clinical Impact Potential of Supplemental Nutrients as Adjuncts of Therapy in High-Risk COVID-19 for Obese Patients

Şahin

Orhan

Uckun³

et al. 2020

Front. Nutr.

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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) in China at the end of 2019 caused a major global pandemic and continues to be an unresolved global health crisis. The supportive care interventions for reducing the severity of symptoms along with participation in clinical trials of investigational treatments are the mainstay of COVID-19 management because there is no effective standard therapy for COVID-19. The comorbidity of COVID-19 rises in obese patients. Micronutrients may boost the host immunity against viral infections, including COVID-19. In this review, we discuss the clinical impact potential of supplemental nutrients as adjuncts of therapy in high-risk COVID-19 for obese patients.

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Metabolites in a mouse cancer model enhance venous thrombogenicity through the aryl hydrocarbon receptor–tissue factor axis

Abstract: Currently, we have insufficient understanding of venous thromboembolism in cancer patients. In this article, the authors reveal a novel mechanism for colon cancer-associated venous thrombosis using a murine model.

Cited by 33 publications

References 61 publications

Indoxyl Sulfate, a Uremic Endotheliotoxin

Indoxyl Sulfate, a Uremic Endotheliotoxin

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

Clinical Impact Potential of Supplemental Nutrients as Adjuncts of Therapy in High-Risk COVID-19 for Obese Patients

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