Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness

Agbor, Larry N; Elased, Khalid M.; Walker, Mary

doi:10.1016/j.bcp.2011.06.011

Cited by 40 publications

(38 citation statements)

References 48 publications

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“…Studies demonstrate that sustained activation of the AHR by xenobiotics promotes the development of cardiovascular disease, including increasing blood pressure and increasing the progression of atherosclerosis (Dalton et al, 2001;Korashy and El-Kadi, 2006;Kopf et al, 2010). In contrast, genetic deletion of AHR results in low blood pressure (Zhang et al, 2010;Agbor et al, 2011Agbor et al, , 2012. Thus, it has been proposed that constitutive (i.e., physiologic) AHR signaling via an endogenous ligand is cardiovascular protective, whereas sustained (i.e., toxicologic) AHR signaling via xenobiotic ligands promotes cardiovascular disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Role of CYP1A1 in Modulating the Vascular and Blood Pressure Benefits of Omega-3 Polyunsaturated Fatty Acids

Agbor

Wiest

Rothe

et al. 2014

J Pharmacol Exp Ther

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The mechanisms that mediate the cardiovascular protective effects of omega 3 (n-3) polyunsaturated fatty acids (PUFAs) have not been fully elucidated. Cytochrome P450 1A1 efficiently metabolizes n-3 PUFAs to potent vasodilators. Thus, we hypothesized that dietary n-3 PUFAs increase nitric oxide (NO)-dependent blood pressure regulation and vasodilation in a CYP1A1-dependent manner. CYP1A1 wild-type (WT) and knockout (KO) mice were fed an n-3 or n-6 PUFA-enriched diet for 8 weeks and were analyzed for tissue fatty acids and metabolites, NO-dependent blood pressure regulation, NO-dependent vasodilation of acetylcholine (ACh) in mesenteric resistance arterioles, and endothelial NO synthase (eNOS) and phospho-Ser1177-eNOS expression in the aorta. All mice fed the n-3 PUFA diet showed significantly higher levels of n-3 PUFAs and their metabolites, and significantly lower levels of n-6 PUFAs and their metabolites. In addition, KO mice on the n-3 PUFA diet accumulated significantly higher levels of n-3 PUFAs in the aorta and kidney without a parallel increase in the levels of their metabolites. Moreover, KO mice exhibited significantly less NO-dependent regulation of blood pressure on the n-3 PUFA diet and significantly less NO-dependent, ACh-mediated vasodilation in mesenteric arterioles on both diets. Finally, the n-3 PUFA diet significantly increased aortic phospho-Ser1177-eNOS/eNOS ratio in the WT compared with KO mice. These data demonstrate that CYP1A1 contributes to eNOS activation, NO bioavailability, and NO-dependent blood pressure regulation mediated by dietary n-3 PUFAs.

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Section: Discussionmentioning

confidence: 99%

Role of CYP1A1 in Modulating the Vascular and Blood Pressure Benefits of Omega-3 Polyunsaturated Fatty Acids

Agbor

Wiest

Rothe

et al. 2014

J Pharmacol Exp Ther

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“…For instance, skin transplantation is a nonvascularized model, and the AHR is expressed in endothelial cells 44 and has a role in vascular development and endothelial cell function. 45-47 PM exposure may alter revascularization that in turn delays graft rejection.…”

Section: Discussionmentioning

confidence: 99%

Modeling the Effect of the Aryl Hydrocarbon Receptor on Transplant Immunity

Julliard

Fechner

Owens

et al. 2017

Transplantation Direct

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BackgroundExposure to pollutants through inhalation is a risk factor for lung diseases including cancer, asthma, and lung transplant rejection, but knowledge of the effects of inhaled pollutants on pathologies outside of the lung is limited.MethodsUsing the minor-mismatched model of male C57BL/6J (B6) to female B6 skin grafts, recipient mice were treated with an inhaled urban dust particle sample every 3 days before and after grafting. Graft survival time was determined, and analysis of the resulting immune response was performed at time before rejection.ResultsSignificant prolongation of male skin grafts occurred in recipient female mice treated with urban dust particles compared with controls and was found to be dependent on aryl hydrocarbon receptor (AHR) expression in the recipient mouse. T cell responses to the male histocompatibility antigen (H-Y) Dby were not altered by exposure to pollutants. A reduction in the frequency of IFNγ-producing CD4 T cells infiltrating the graft on day 7 posttransplant was observed. Flow cytometry analysis revealed that AHR expression is upregulated in IFNγ-producing CD4 T cells during immune responses in vitro and in vivo.ConclusionsSurprisingly, inhalation of a pollutant standard was found to prolong graft survival in a minor-mismatched skin graft model in an AHR-dependent manner. One possible mechanism may be an effect on IFNγ-producing CD4 T cells responding to donor antigen. The increased expression of AHR in this CD4 T cell subset suggests that AHR ligands within the particulate matter may be directly affecting the type 1 T helper cell response in this model.

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“…114 Hypotensive AhR −/− mice exhibit a significantly higher level of endothelial nitric oxide synthase (eNOS) and enhanced vascular nitric oxide (NO) production. 115 TCDD exposure of ECs increases the production of ROS, and decreases acetylcholine-stimulated NO production by inducing CYP1A1 and CYP1B1. 116 AhR could serve as a target in the treatment of high blood pressure and other NO-dependent glucose homeostasis and bile acid metabolism.…”

Section: Clinical Importance Of Pxr Car and Ahrmentioning

confidence: 94%