TRAIL protects against endothelial dysfunction in vivo and inhibits angiotensin-II-induced oxidative stress in vascular endothelial cells in vitro
TRAIL protects against endothelial dysfunction in vivo and inhibits angiotensin-II-induced oxidative stress in vascular endothelial cells in vitro
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DOI：
10.1016/j.freeradbiomed.2018.08.031
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发表时间：
2018-10-01
影响因子：
7.4
通讯作者：
Kavurma, Mary M.
中科院分区：
文献类型：
--
作者：
Cholan, Pradeep Manuneedhi;Cartland, Sian P.;Kavurma, Mary M.
血管内皮细胞对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，其中活性氧（ROS）介导的氧化应激起主要作用。肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）在动脉粥样硬化中的保护作用日益被认识到，然而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和改善内皮细胞（EC）功能。在冠状动脉疾病患者中，与健康个体相比，血浆TRAIL水平显著降低，并且与循环8-异前列腺素F-2 α（体内氧化应激的标志物）水平呈负相关。在体内，高脂喂养的动脉粥样硬化Trail（-/-）Apoe（-/-）小鼠在内皮依赖性血管舒张方面表现出显著损伤，与Apoe（-/-）小鼠相比，这与血管ROS和4-羟基壬烯醛增加相关。与野生型小鼠相比，Trail（-/-）小鼠的几个器官中通过Evan's蓝染料外渗测量的内皮渗透性增加，这与VE-钙粘蛋白表达的减少相关。在体外EC中，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生成被TRAIL预处理抑制。此外，血管紧张素Ⅱ增强VCAM-1的表达和单核细胞粘附内皮细胞被抑制的TRAIL。最后，AngII降低了VE-钙粘蛋白的表达并重新分布该蛋白，所有这些都通过TRAIL预处理回到基线。这些研究结果首次证明，TRAIL保护对几种形式的内皮功能障碍，涉及其控制EC ROS生成的能力。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，以改善内皮功能和动脉粥样硬化。
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-2 alpha, a marker of in vivo oxidative stress. In vivo, high-fat fed, atherosclerotic Trail(-/-)Apoe(-/-) 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.