1. Aryl hydrocarbon receptor (AhR) activation contributes to high-fat diet-induced vascular dysfunction.
- Author
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da Silva JF, Bolsoni JA, da Costa RM, Alves JV, Bressan AFM, Silva LEV, Costa TJ, Oliveira AER, Manzato CP, Aguiar CA, Fazan R Jr, Cunha FQ, Nakaya HI, Carneiro FS, and Tostes RC
- Subjects
- Animals, Endothelial Cells metabolism, Endothelium, Vascular, Male, Mice, Mice, Inbred C57BL, Obesity metabolism, Vasodilation physiology, Diet, High-Fat adverse effects, Receptors, Aryl Hydrocarbon genetics, Receptors, Aryl Hydrocarbon metabolism
- Abstract
Background and Purpose: Metabolic and vascular dysfunction are common features of obesity. Aryl hydrocarbon receptor (AhR) regulates lipid metabolism and vascular homeostasis, but whether vascular AhR are activated in obesity or have a protective and/or harmful effects on vascular function in obesity are unknown. Our study addresses whether AhR activation contributes to obesity-associated vascular dysfunction and the mechanisms involved in these AhR effects., Experimental Approach: Male AhR KO (Ahr
-/- ) and WT mice were fed either control or a HF (high-fat) diet for 10 weeks. Metabolic and inflammatory parameters were measured in serum and adipose tissue. Vascular reactivity (isometric force) was evaluated using a myography. Endothelial NOS (eNOS) and AhR protein expression was determined by western blot, Cyp1A1 and Nos3 gene expression by RT-PCR and.NO production was quantified by DAF fluorescence., Key Results: HF diet increased total serum HDL and LDL, as well as vascular AhR protein expression and proinflammatory cytokines in the adipose tissue. HF diet decreased endothelium-dependent vasodilation. AhR deletion protected mice from HF diet-induced dyslipidaemia, weight gain and inflammatory processes. HF diet-induced endothelial dysfunction was attenuated in Ahr-/- mice. Vessels from Ahr-/- mice exhibited a greater NO reserve. In cultured endothelial cells, lysophosphatidylcholine (LPC) a major component of LDL and oxidized LDL [oxLDL]) reduced Nos3 gene expression and NO production. Antagonism of the AhR inhibited LPC effects on endothelial cells and induced decreased endothelium-dependent vasodilation., Conclusion and Implications: AhR deletion attenuates HF diet-induced dyslipidaemia and vascular dysfunction by improving eNOS/NO signalling. Targeting AhRs may prevent obesity-associated vascular dysfunction., (© 2022 The British Pharmacological Society.)- Published
- 2022
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