Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Special Academic Unit of Health Sciences, Federal University of Jataí, Jataí, Brazil.
Front Immunol. 2020 Jul 31;11:1647. doi: 10.3389/fimmu.2020.01647. eCollection 2020.
Both supraphysiological and subphysiological testosterone levels are associated with increased cardiovascular risk. Testosterone consumption at supraphysiological doses has been linked to increased blood pressure, left ventricular hypertrophy, vascular dysfunction, and increased levels of inflammatory markers. Activation of the NLRP3 inflammasome contributes to the production of proinflammatory cytokines, leading to cardiovascular dysfunction. We hypothesized that supraphysiological levels of testosterone, via generation of mitochondrial reactive oxygen species (mROS), activates the NLRP3 inflammasome and promotes vascular dysfunction. Male, 12 week-old C57Bl/6J (WT) and NLRP3 knockout (NLRP3) mice were used. Mice were treated with testosterone propionate [TP (10 mg/kg) ] or vehicle for 30 days. In addition, vessels were incubated with testosterone [Testo (10 M, 2 h) ]. Testosterone levels, blood pressure, vascular function (thoracic aortic rings), pro-caspase-1/caspase-1 and interleukin-1β (IL-1β) expression, and generation of reactive oxygen species were determined. Testosterone increased contractile responses and reduced endothelium-dependent vasodilation, both and . These effects were not observed in arteries from NLRP3 mice. Aortas of TP-treated WT mice (), as well as aortas from WT mice incubated with testo (), exhibited increased mROS levels and increased caspase-1 and IL-1β expression. These effects were not observed in arteries from NLRP3 mice. Flutamide [Flu, 10 M, androgen receptor (AR) antagonist], carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 10 M, mitochondrial uncoupler) and MCC950 (MCC950, 10 M, a NLRP3 receptor inhibitor) prevented testosterone-induced mROS generation. Supraphysiological levels of testosterone induce vascular dysfunction via mROS generation and NLRP3 inflammasome activation. These events may contribute to increased cardiovascular risk.
无论是生理性或低于生理性的睾丸酮水平都与心血管风险增加相关。超生理剂量的睾丸酮摄入与血压升高、左心室肥厚、血管功能障碍和炎症标志物水平升高有关。NLRP3 炎性小体的激活导致促炎细胞因子的产生，导致心血管功能障碍。我们假设，通过生成线粒体活性氧（mROS），超生理水平的睾丸酮激活 NLRP3 炎性小体并促进血管功能障碍。雄性，12 周龄 C57Bl/6J（WT）和 NLRP3 敲除（NLRP3）小鼠用于实验。小鼠用丙酸睾丸酮（TP）[TP（10mg/kg）]或载体处理 30 天。此外，用睾丸酮[Testo（10M，2h）]孵育血管。测定睾丸酮水平、血压、血管功能（胸主动脉环）、前半胱天冬酶-1/半胱天冬酶-1 和白细胞介素-1β（IL-1β）表达以及活性氧的产生。睾丸酮增加了收缩反应并降低了内皮依赖性血管舒张，两者均为。这些作用在 NLRP3 小鼠的动脉中没有观察到。TP 处理的 WT 小鼠的主动脉（）以及用 testo 孵育的 WT 小鼠的主动脉（）表现出增加的 mROS 水平和增加的半胱天冬酶-1 和 IL-1β表达。这些作用在 NLRP3 小鼠的动脉中没有观察到。氟他胺[Flu，10M，雄激素受体（AR）拮抗剂]、羰基氰化物 m-氯代苯腙（CCCP，10M，线粒体解偶联剂）和 MCC950（MCC950，10M，NLRP3 受体抑制剂）可防止睾丸酮诱导的 mROS 生成。超生理水平的睾丸酮通过 mROS 生成和 NLRP3 炎性小体激活诱导血管功能障碍。这些事件可能导致心血管风险增加。
