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, Cunha Fernando Q, Nakaya Helder I, Carneiro Fernando S, Tostes Rita C
Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil.
Academic Unit on Health Sciences, Jataí Federal University, Jataí, Brazil.
Br J Pharmacol. 2022 Jun;179(12):2938-2952. doi: 10.1111/bph.15789. Epub 2022 Feb 17.
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.
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.
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.
AhR deletion attenuates HF diet-induced dyslipidaemia and vascular dysfunction by improving eNOS/NO signalling. Targeting AhRs may prevent obesity-associated vascular dysfunction.
代谢和血管功能障碍是肥胖的常见特征。芳烃受体（AhR）调节脂质代谢和血管稳态，但肥胖时血管中的AhR是否被激活，以及其对肥胖时血管功能是具有保护作用还是有害作用尚不清楚。我们的研究旨在探讨AhR激活是否会导致肥胖相关的血管功能障碍以及这些AhR效应所涉及的机制。
雄性AhR基因敲除（Ahr-/-）小鼠和野生型（WT）小鼠分别喂食对照饮食或高脂（HF）饮食10周。检测血清和脂肪组织中的代谢和炎症参数。使用血管张力测定法评估血管反应性（等长力）。通过蛋白质印迹法测定内皮型一氧化氮合酶（eNOS）和AhR蛋白表达，通过逆转录聚合酶链反应（RT-PCR）测定Cyp1A1和Nos3基因表达，并通过DAF荧光定量一氧化氮（NO）生成。
高脂饮食增加了血清总高密度脂蛋白（HDL）和低密度脂蛋白（LDL），以及脂肪组织中血管AhR蛋白表达和促炎细胞因子。高脂饮食降低了内皮依赖性血管舒张。AhR基因缺失使小鼠免受高脂饮食诱导的血脂异常、体重增加和炎症过程的影响。高脂饮食诱导的内皮功能障碍在Ahr-/-小鼠中有所减轻。Ahr-/-小鼠的血管表现出更大的NO储备。在培养的内皮细胞中，低密度脂蛋白（LDL）和氧化型低密度脂蛋白（oxLDL）的主要成分溶血磷脂酰胆碱（LPC）降低了Nos3基因表达和NO生成。AhR的拮抗作用抑制了LPC对内皮细胞的作用，并导致内皮依赖性血管舒张减弱。
AhR基因缺失通过改善eNOS/NO信号传导减轻高脂饮食诱导的血脂异常和血管功能障碍。靶向AhR可能预防肥胖相关的血管功能障碍。
