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Hypertension, Cardiac Hypertrophy, and Impaired Vascular Relaxation Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin are Associated with Increased Superoxide

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Abstract

The mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the incidence of human cardiovascular disease are not known. We investigated the degree to which cardiovascular disease develops in mice following subchronic TCDD exposure. Adult male C57BL/6 mice were dosed with vehicle or 300 ng TCDD/kg by oral gavage three times per week for 60 days. Blood pressure was recorded by radiotelemetry and aortic endothelial function was assessed by acetylcholine-induced vasorelaxation. Mean arterial pressure of TCDD-exposed mice was increased significantly by day 4 and between days 7–10, 25–35, and 45–60 with two periods of normalization on days 11–24 and days 36–39. Consistent with a prolonged period of systemic hypertension, heart weight was increased and was associated with concentric left ventricular hypertrophy. Significant increases in superoxide production also were observed in the kidney, heart, and aorta of TCDD-exposed mice. Furthermore, increased aortic superoxide resulted in endothelial dysfunction as demonstrated by significant impairment of acetylcholine-induced vasorelaxation in TCDD-exposed mice, which was restored by tempol, a superoxide dismutase (SOD) mimetic. Our model is the first to definitely demonstrate that sustained AhR activation by TCDD increases blood pressure and induces cardiac hypertrophy, which may be mediated, in part, by increased superoxide.

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Acknowledgments

Funding National Institute of Health (ES12335 and HL078914 to MKW, ES12072 to UNM, 5T32HL007736 to UNM). Phillip Kopf is recognized as an American Foundation for Pharmaceutical Education Pre-Doctoral Fellow. The authors thank Drs. Nancy L. Kanagy and Matthew J. Campen for their valuable assistance.

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  1. College of Pharmacy, University of New Mexico Health Sciences Center, MSC09 5360, 2502 Marble NE, Albuquerque, NM, 87131, USA

    Phillip G. Kopf & Mary K. Walker

  2. Biosciences Research Laboratory, Agricultural Research Station, United States Department of Agriculture, Fargo, ND, 58105, USA

    Janice K. Huwe

  3. Department of Cell Biology and Physiology, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA

    Mary K. Walker

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  1. Phillip G. Kopf
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Kopf, P.G., Huwe, J.K. & Walker, M.K. Hypertension, Cardiac Hypertrophy, and Impaired Vascular Relaxation Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin are Associated with Increased Superoxide. Cardiovasc Toxicol 8, 181–193 (2008). https://doi.org/10.1007/s12012-008-9027-x

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