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Aryl hydrocarbon receptor (AhR) activation contributes to high-fat diet-induced vascular dysfunction.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2022 Jun; Vol. 179 (12), pp. 2938-2952. Date of Electronic Publication: 2022 Feb 17. - Publication Year :
- 2022
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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.<br />Experimental Approach: Male AhR KO (Ahr <superscript>-/-</superscript> ) 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.<br />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 <superscript>-/-</superscript> mice. Vessels from Ahr <superscript>-/-</superscript> 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.<br />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.<br /> (© 2022 The British Pharmacological Society.)
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 179
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 34978070
- Full Text :
- https://doi.org/10.1111/bph.15789