Aryl hydrocarbon receptor (AhR) activation contributes to high-fat diet-induced vascular dysfunction

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da Silva, Josiane Fernandes ; Bolsoni, Juliana A. ; da Costa, Rafael M. ; Alves, Juliano, V ; Bressan, Alecsander F. M. ; Silva, Luiz Eduardo, V ; Costa, Tiago J. ; Oliveira, Antonio E. R. ; Manzato, Carla P. ; Aguiar, Carlos A. ; Fazan, Rubens, Jr. ; Cunha, Fernando Q. ; Nakaya, Helder, I ; Carneiro, Fernando S. ; Tostes, Rita C.

• Tipo de documento: Artigo Científico
• Fonte: British Journal of Pharmacology; v. 179, n. 12, p. 15-pg., 2022-02-17.

Resumo

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. (AU)

• Processo FAPESP: 18/21199-3 - Avaliação da participação dos receptores para hidrocarboneto de arila (AhR) na disfunção vascular de camundongos alimentados com dieta hiperlipídica: papel do sistema renina angiotensina (SRA)
• Beneficiário: Juliana de Andrade Bolsoni
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/22579-7 - Biologia de sistemas aplicada a análise transcriptômica de doenças inflamatórias
• Beneficiário: Antonio Edson Rocha Oliveira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/16207-1 - Centro de Pesquisa em Doenças Inflamatórias - CRID
• Beneficiário: Josiane Fernandes da Silva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado