内皮素-1 下调核因子红细胞 2 相关因子-2,导致肥胖症患者血管周围脂肪组织功能障碍。

IF 6.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Anna Flavia R Lima, Daniel Rodrigues, Mirele R Machado, José Teles Oliveira-Neto, Alecsander F M Bressan, Carina A Pedersoli, Juliano V Alves, Júlio A Silva-Neto, Paula R Barros, Thiago B Dias, Luis V Garcia, Ariane Bruder-Nascimento, Thiago Bruder-Nascimento, Fernando S Carneiro, Luiz Osório S Leiria, Rita C Tostes, Rafael M Costa
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引用次数: 0

摘要

血管周围脂肪组织(PVAT)对血管肌肉收缩有负面调节作用。然而,在肥胖的情况下,血管周围脂肪组织会释放血管收缩物质,从而对血管功能产生不利影响。在这种情况下,多肽内皮素-1(ET-1)起着关键作用,它会诱发氧化应激,破坏血管功能。本研究推测肥胖会增加 PVAT 中 ET-1 的产生,降低核因子红细胞 2 相关因子-2(Nrf2)转录因子的功能,进一步增加活性氧(ROS)的生成,最终导致 PVAT 功能障碍。雄性 C57BL/6 小鼠以标准或高脂肪饮食喂养 16 周。小鼠还接受了为期 7 天的生理盐水或每日剂量为 100 mg.kg-1 的 ETA 和 ETB 受体拮抗剂波生坦治疗。在有 PVAT 和没有 PVAT 的胸主动脉环上对血管功能进行了评估。机理研究利用了所有组的 PVAT 和培养的 WT-1 小鼠棕色脂肪细胞。肥胖小鼠的 PVAT 表现出 ET-1 生成增加、ECE1 和 ETA 基因表达增加、抗收缩效应丧失,以及 ROS 生成增加、Nrf2 活性降低和 Nrf2 靶向抗氧化基因表达下调。肥胖小鼠的腹皮下组织还表现出 Tyr216 磷酸化-GSK3β 和 KEAP1 的表达增加,但 Nrf2 负调控因子 BACH1 却没有增加。波生坦治疗可逆转所有这些影响。同样,ET-1 增加了棕色脂肪细胞中 ROS 的生成并降低了 Nrf2 的活性,而 BQ123(ETA 受体拮抗剂)可减轻这些影响。这些研究结果表明,ET-1 是导致肥胖症 PVAT 功能障碍的主要因素,并强调通过药物控制 ET-1 的作用可恢复 PVAT 对心血管的保护作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Endothelin-1 down-regulates nuclear factor erythroid 2-related factor-2 and contributes to perivascular adipose tissue dysfunction in obesity.

Perivascular adipose tissue (PVAT) negatively regulates vascular muscle contraction. However, in the context of obesity, the PVAT releases vasoconstrictor substances that detrimentally affect vascular function. A pivotal player in this scenario is the peptide endothelin-1 (ET-1), which induces oxidative stress and disrupts vascular function. The present study postulates that obesity augments ET-1 production in the PVAT, decreases the function of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, further increasing reactive oxygen species (ROS) generation, culminating in PVAT dysfunction. Male C57BL/6 mice were fed either a standard or a high-fat diet for 16 weeks. Mice were also treated with saline or a daily dose of 100 mg·kg-1 of the ETA and ETB receptor antagonist Bosentan, for 7 days. Vascular function was evaluated in thoracic aortic rings, with and without PVAT. Mechanistic studies utilized PVAT from all groups and cultured WT-1 mouse brown adipocytes. PVAT from obese mice exhibited increased ET-1 production, increased ECE1 and ETA gene expression, loss of the anticontractile effect, as well as increased ROS production, decreased Nrf2 activity, and downregulated expression of Nrf2-targeted antioxidant genes. PVAT of obese mice also exhibited increased expression of Tyr216-phosphorylated-GSK3β and KEAP1, but not BACH1 - negative Nrf2 regulators. Bosentan treatment reversed all these effects. Similarly, ET-1 increased ROS generation and decreased Nrf2 activity in brown adipocytes, events mitigated by BQ123 (ETA receptor antagonist). These findings place ET-1 as a major contributor to PVAT dysfunction in obesity and highlight that pharmacological control of ET-1 effects restores PVAT's cardiovascular protective role.

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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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