Costa Rafael M, Alves-Lopes Rhéure, Alves Juliano V, Servian Carolina P, Mestriner Fabíola L, Carneiro Fernando S, Lobato Núbia de S, Tostes Rita C
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Academic Unit of Health Sciences, Federal University of Jatai, Jatai, Brazil.
Front Physiol. 2022 Mar 8;13:837603. doi: 10.3389/fphys.2022.837603. eCollection 2022.
Obesity, an important risk factor for cardiovascular disease, promotes vascular oxidative stress. Considering that free testosterone levels remain within the reference range, especially in obese young men and that testosterone stimulates reactive oxygen species (ROS) generation, we sought to investigate whether testosterone interferes with obesity-associated oxidative stress and vascular dysfunction in male mice. We hypothesized that testosterone favors ROS accumulation and vascular dysfunction in high fat diet (HFD)-fed obese mice. We also questioned whether testosterone downregulates the nuclear factor E2-related factor 2 (Nrf2), one of the major cellular defense mechanisms against oxidative stimuli. Male C57Bl/6J mice were submitted to orchiectomy or sham-operation. Mice received either a control diet (CD) or HFD for 18 weeks. Vascular function was assessed in thoracic aortic rings and molecular mechanisms by which testosterone contributes to vascular dysfunction were determined. HFD reduced acetylcholine-induced vasodilation and increased vascular ROS generation in sham mice. Castration prevented these effects. Treatment of castrated mice fed either the CD or HFD with testosterone propionate decreased acetylcholine vasodilation. HFD decreased Nrf2 nuclear accumulation, events linked to decreased mRNA expression and activity of Nrf2-regulated enzymes (catalase, heme oxygenase-1, peroxiredoxin, and thioredoxin). These events were prevented in HFD-fed castrated mice. Bardoxolone, a Nrf2 activator, increased nuclear accumulation of Nrf2, decreased ROS generation and improved acetylcholine vasodilation in HFD-fed sham mice. , testosterone increased ROS generation and decreased Nrf2 nuclear accumulation. These effects were prevented in the presence of an androgen receptor antagonist, an inhibitor of gene transcription and an inhibitor of the pro-oxidant enzyme NOX-1. These results indicate that testosterone downregulates Nrf2, leading to oxidative stress and vascular dysfunction in HFD-fed obese young mice.
肥胖是心血管疾病的一个重要危险因素，会促进血管氧化应激。鉴于游离睾酮水平保持在参考范围内，尤其是在肥胖的年轻男性中，并且睾酮会刺激活性氧（ROS）的产生，我们试图研究睾酮是否会干扰雄性小鼠中与肥胖相关的氧化应激和血管功能障碍。我们假设睾酮有利于高脂饮食（HFD）喂养的肥胖小鼠中ROS的积累和血管功能障碍。我们还质疑睾酮是否会下调核因子E2相关因子2（Nrf2），这是对抗氧化刺激的主要细胞防御机制之一。雄性C57Bl/6J小鼠接受去势手术或假手术。小鼠接受对照饮食（CD）或HFD喂养18周。评估胸主动脉环的血管功能，并确定睾酮导致血管功能障碍的分子机制。HFD降低了假手术小鼠中乙酰胆碱诱导的血管舒张，并增加了血管ROS的产生。去势可预防这些影响。用丙酸睾酮治疗喂食CD或HFD的去势小鼠会降低乙酰胆碱血管舒张。HFD降低了Nrf2的核积累，这些事件与Nrf2调节的酶（过氧化氢酶、血红素加氧酶-1、过氧化物酶和硫氧还蛋白）的mRNA表达和活性降低有关。这些事件在喂食HFD的去势小鼠中得到预防。巴多昔芬，一种Nrf2激活剂，增加了喂食HFD的假手术小鼠中Nrf2的核积累，减少了ROS的产生，并改善了乙酰胆碱血管舒张。睾酮增加了ROS的产生并减少了Nrf2的核积累。在存在雄激素受体拮抗剂、基因转录抑制剂和促氧化酶NOX-1抑制剂的情况下，这些影响得到预防。这些结果表明，睾酮下调Nrf2，导致喂食HFD的肥胖年轻小鼠出现氧化应激和血管功能障碍。
