2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression
- 113 Downloads
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.
KeywordsAngiotensinogen Cytochrome P4501A1 Perivascular adipose tissue (PVAT) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Vascular dysfunction Nitric oxide
We thank Emily Wheeler and Meera Shah for their expert technical support. This work was support by Teva Pharmaceutical Industries Ltd., Netanya, Israel [DS-2018-003].
- 14.Kim, D., Aizawa, T., Wei, H., Pi, X., Rybalkin, S. D., Berk, B. C., et al. (2005). Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling. Journal of Molecular and Cellular Cardiology, 38, 175–184.CrossRefGoogle Scholar
- 26.Schwarz, D., Kisselev, P., Ericksen, S. S., Szklarz, G. D., Chernogolov, A., Honeck, H., et al. (2004). Arachidonic and eicosapentaenoic acid metabolism by human CYP1A1: highly stereoselective formation of 17(R),18(S)-epoxyeicosatetraenoic acid. Biochemical Pharmacology, 67, 1445–1457.CrossRefGoogle Scholar
- 28.Siriwardhana, N., Kalupahana, N. S., Fletcher, S., Xin, W., Claycombe, K. J., Quignard-Boulange, A., et al. (2012). n-3 and n-6 polyunsaturated fatty acids differentially regulate adipose angiotensinogen and other inflammatory adipokines in part via NF-kappaB-dependent mechanisms. Journal of Nutritional Biochemistry, 23, 1661–1667.CrossRefGoogle Scholar
- 31.Wiest, E. F., Walsh-Wilcox, M. T., Rothe, M., Schunck, W. H., & Walker, M. K. (2016). Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin. Toxicological Sciences, 154, 43–54.CrossRefGoogle Scholar
- 32.Yang, J., Solaimani, P., Dong, H., Hammock, B., & Hankinson, O. (2013). Treatment of mice with 2,3,7,8-Tetrachlorodibenzo-p-dioxin markedly increases the levels of a number of cytochrome P450 metabolites of omega-3 polyunsaturated fatty acids in the liver and lung. Journal of Toxicological Sciences, 38, 833–836.CrossRefGoogle Scholar