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2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression.

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction. TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction.

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  • Authors+Show Affiliations

    ,

    Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, 2703 Frontier Ave NE MSC09 5630, Albuquerque, NM, 87131, USA.

    ,

    Teva Pharmaceutical Industries Ltd, Netanya, Israel. Ayala Targeted Therapies, Rehovot, Israel.

    ,

    Teva Pharmaceutical Industries Ltd, Netanya, Israel.

    Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, 2703 Frontier Ave NE MSC09 5630, Albuquerque, NM, 87131, USA. mwalker@salud.unm.edu.

    Source

    Cardiovascular toxicology : 2019 May 21 pg

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31115867

    Citation

    Walsh-Wilcox, Mary T., et al. "2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That Is Dependent On Perivascular Adipose and Cytochrome P4501A1 Expression." Cardiovascular Toxicology, 2019.
    Walsh-Wilcox MT, Kaye J, Rubinstein E, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression. Cardiovasc Toxicol. 2019.
    Walsh-Wilcox, M. T., Kaye, J., Rubinstein, E., & Walker, M. K. (2019). 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression. Cardiovascular Toxicology, doi:10.1007/s12012-019-09529-6.
    Walsh-Wilcox MT, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That Is Dependent On Perivascular Adipose and Cytochrome P4501A1 Expression. Cardiovasc Toxicol. 2019 May 21; PubMed PMID: 31115867.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression. AU - Walsh-Wilcox,Mary T, AU - Kaye,Joel, AU - Rubinstein,Efrat, AU - Walker,Mary K, Y1 - 2019/05/21/ PY - 2019/5/23/entrez KW - 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) KW - Angiotensinogen KW - Cytochrome P4501A1 KW - Nitric oxide KW - Perivascular adipose tissue (PVAT) KW - Vascular dysfunction JF - Cardiovascular toxicology JO - Cardiovasc. Toxicol. N2 - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction. TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction. SN - 1559-0259 UR - https://www.unboundmedicine.com/medline/citation/31115867/2,3,7,8-Tetrachlorodibenzo-p-dioxin_Induces_Vascular_Dysfunction_That_is_Dependent_on_Perivascular_Adipose_and_Cytochrome_P4501A1_Expression L2 - https://dx.doi.org/10.1007/s12012-019-09529-6 DB - PRIME DP - Unbound Medicine ER -