Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Department of Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Br J Pharmacol. 2017 Oct;174(20):3527-3541. doi: 10.1111/bph.13687. Epub 2017 Jan 12.
Obesity is associated with structural and functional changes in perivascular adipose tissue (PVAT), favouring release of reactive oxygen species (ROS), vasoconstrictor and proinflammatory factors. The cytokine TNF-α induces vascular dysfunction and is produced by PVAT. We tested the hypothesis that obesity-associated PVAT dysfunction was mediated by augmented mitochondrial ROS (mROS) generation due to increased TNF-α production in this tissue.
C57Bl/6J and TNF-α receptor-deficient mice received control or high fat diet (HFD) for 18 weeks. We used pharmacological tools to determine the participation of mROS in PVAT dysfunction. Superoxide anion (O ) and H O were assayed in PVAT and aortic rings were used to assess vascular function.
Aortae from HFD-fed obese mice displayed increased contractions to phenylephrine and loss of PVAT anti-contractile effect. Inactivation of O , dismutation of mitochondria-derived H O , uncoupling of oxidative phosphorylation and Rho kinase inhibition, decreased phenylephrine-induced contractions in aortae with PVAT from HFD-fed mice. O and H O were increased in PVAT from HFD-fed mice. Mitochondrial respiration analysis revealed decreased O consumption rates in PVAT from HFD-fed mice. TNF-α inhibition reduced H O levels in PVAT from HFD-fed mice. PVAT dysfunction, i.e. increased contraction to phenylephrine in PVAT-intact aortae, was not observed in HFD-obese mice lacking TNF-α receptors. Generation of H O was prevented in PVAT from TNF-α receptor deficient obese mice.
TNF-α-induced mitochondrial oxidative stress is a key and novel mechanism involved in obesity-associated PVAT dysfunction. These findings elucidate molecular mechanisms whereby oxidative stress in PVAT could affect vascular function.
This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.
肥胖与血管周围脂肪组织（PVAT）的结构和功能变化有关，有利于活性氧（ROS）、血管收缩和促炎因子的释放。细胞因子 TNF-α 可诱导血管功能障碍，并由 PVAT 产生。我们检验了这样一个假设，即肥胖相关的 PVAT 功能障碍是由于该组织中 TNF-α 产生增加导致线粒体 ROS（mROS）生成增加而介导的。
C57Bl/6J 和 TNF-α 受体缺陷型小鼠接受对照或高脂肪饮食（HFD）喂养 18 周。我们使用药理学工具来确定 mROS 在 PVAT 功能障碍中的参与程度。在 PVAT 中测定超氧阴离子（O ）和 H O ，并使用主动脉环评估血管功能。
HFD 喂养肥胖小鼠的主动脉对苯肾上腺素的收缩反应增加，PVAT 抗收缩作用丧失。O 的失活、线粒体衍生的 H O 的歧化、氧化磷酸化的解偶联和 Rho 激酶抑制，降低了 HFD 喂养小鼠的主动脉中苯肾上腺素诱导的收缩。HFD 喂养小鼠的 PVAT 中 O 和 H O 增加。线粒体呼吸分析显示 HFD 喂养小鼠的 PVAT 中 O 消耗率降低。TNF-α 抑制降低了 HFD 喂养小鼠的 PVAT 中 H O 水平。在缺乏 TNF-α 受体的 HFD 肥胖小鼠中，没有观察到 PVAT 功能障碍（即 PVAT 完整的主动脉中对苯肾上腺素的收缩增加）。TNF-α 受体缺陷肥胖小鼠的 PVAT 中 H O 的生成被阻止。
TNF-α 诱导的线粒体氧化应激是肥胖相关的 PVAT 功能障碍的一个关键和新的机制。这些发现阐明了 PVAT 中的氧化应激如何影响血管功能的分子机制。
本文是关于“调节血管周围脂肪组织的分子机制-潜在的治疗靶点？”这一主题部分的文章。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.
