Heart Research Institute, Sydney 2042, Australia; Sydney Medical School, The University of Sydney, Sydney 2006, Australia.
School of Medical Sciences, University of New South Wales, Sydney 2052, Australia.
Free Radic Biol Med. 2018 Oct;126:341-349. doi: 10.1016/j.freeradbiomed.2018.08.031. Epub 2018 Aug 27.
The vascular endothelium is critical for maintenance of cardiovascular homeostasis. Endothelial dysfunction is a key event of atherosclerosis, with oxidative stress mediated by reactive oxygen species (ROS) playing a major role. Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is increasingly recognised to play a protective role in atherosclerosis, however the molecular mechanisms by which it exerts its beneficial effects are unclear. Here we examined if TRAIL could attenuate vascular oxidative stress and improve endothelial cell (EC) function. In coronary artery disease patients, plasma TRAIL levels were significantly reduced compared to healthy individuals, and negatively correlated with the levels of circulating 8-iso Prostaglandin F, a marker of in vivo oxidative stress. In vivo, high-fat fed, atherosclerotic TrailApoe mice exhibited a significant impairment in endothelial-dependent vasorelaxation, which correlated with increased vascular ROS and 4-hydroxynonenal compared to Apoe mice. Endothelial permeability measured by Evan's blue dye extravasation was increased in several organs of Trail mice compared to wild-type mice, which correlated with a decrease in VE-cadherin expression. In vitro in ECs, angiotensin II (AngII)-induced ROS generation involving the mitochondria, NADPH oxidase-4 (NOX-4) and eNOS, was inhibited by pre-treatment with TRAIL. Furthermore, AngII-augmented VCAM-1 expression and monocyte adhesion to ECs was inhibited by TRAIL. Finally, AngII reduced VE-cadherin expression and redistributed this protein, all of which was brought back to baseline by TRAIL pre-treatment. These findings demonstrate for the first time that TRAIL protects against several forms of endothelial dysfunction involving its ability to control EC ROS generation. Understanding the role TRAIL plays in normal physiology and disease, may lead to potential new therapies to improve endothelial function and atherosclerosis.
血管内皮对于维持心血管稳态至关重要。内皮功能障碍是动脉粥样硬化的关键事件，活性氧（ROS）介导的氧化应激起着主要作用。肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）在动脉粥样硬化中越来越被认为具有保护作用，但其发挥有益作用的分子机制尚不清楚。在这里，我们研究了 TRAIL 是否可以减轻血管氧化应激并改善内皮细胞（EC）功能。与健康个体相比，冠心病患者的血浆 TRAIL 水平显著降低，并且与循环 8-异前列腺素 F 的水平呈负相关，8-异前列腺素 F 是体内氧化应激的标志物。在体内，高脂肪喂养的动脉粥样硬化 TrailApoe 小鼠表现出明显的内皮依赖性血管舒张功能障碍，与 Apoe 小鼠相比，血管 ROS 和 4-羟壬烯醛增加相关。与野生型小鼠相比，几种器官的 Trail 小鼠的内皮通透性通过 Evan's 蓝染料渗出增加，这与 VE-钙粘蛋白表达减少相关。在体外的 EC 中，TRAIL 预处理可抑制血管紧张素 II（AngII）诱导的涉及线粒体、NADPH 氧化酶-4（NOX-4）和 eNOS 的 ROS 生成。此外，TRAIL 抑制了 AngII 增强的 VCAM-1 表达和单核细胞与 EC 的黏附。最后，AngII 降低了 VE-钙粘蛋白的表达并重新分布了这种蛋白，所有这些都通过 TRAIL 预处理恢复到基线。这些发现首次表明，TRAIL 通过控制 ECROS 的生成来保护多种形式的内皮功能障碍。了解 TRAIL 在正常生理和疾病中的作用，可能会导致潜在的新疗法来改善内皮功能和动脉粥样硬化。
