Savira Feby, Kompa Andrew R, Magaye Ruth, Xiong Xin, Huang Li, Jucker Beat M, Willette Robert N, Kelly Darren J, Wang Bing H
Biomarker Discovery, Baker Heart and Diabetes Institute, Melbourne, Australia; Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
Centre of Cardiovascular Research and Education in Therapeutics, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia.
Life Sci. 2021 May 1;272:119267. doi: 10.1016/j.lfs.2021.119267. Epub 2021 Feb 22.
Indoxyl sulfate (IS), a protein-bound uremic toxin, is implicated in endothelial dysfunction, which contributes to adverse cardiovascular events in chronic kidney disease. Apoptosis signal regulating kinase 1 (ASK1) is a reactive oxygen species-driven kinase involved in IS-mediated adverse effects. This study assessed the therapeutic potential of ASK1 inhibition in alleviating endothelial effects induced by IS.
IS, in the presence and absence of a selective ASK1 inhibitor (GSK2261818A), was assessed for its effect on vascular reactivity in rat aortic rings, and cultured human aortic endothelial cells where we evaluated phenotypic and mechanistic changes.
IS directly impairs endothelium-dependent vasorelaxation and endothelial cell migration. Mechanistic studies revealed increased production of reactive oxygen species-related markers, reduction of endothelial nitric oxide synthase and increased protein expression of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). IS also increases angiopoietin-2 and tumour necrosis factor α gene expression and promotes transforming growth factor β receptor abundance. Inhibition of ASK1 ameliorated the increase in oxidative stress markers, promoted autocrine interleukin 8 pro-angiogenic signalling and decreased anti-angiogenic responses at least in part via reducing TIMP1 protein expression.
ASK1 inhibition attenuated vasorelaxation and endothelial cell migration impaired by IS. Therefore, ASK1 is a viable intracellular target to alleviate uremic toxin-induced impairment in the vasculature.
硫酸吲哚酚（IS）是一种与蛋白质结合的尿毒症毒素，与内皮功能障碍有关，而内皮功能障碍会导致慢性肾脏病患者发生不良心血管事件。凋亡信号调节激酶1（ASK1）是一种由活性氧驱动的激酶，参与IS介导的不良反应。本研究评估了抑制ASK1在减轻IS诱导的内皮效应方面的治疗潜力。
在存在和不存在选择性ASK1抑制剂（GSK2261818A）的情况下，评估IS对大鼠主动脉环血管反应性的影响，并在培养的人主动脉内皮细胞中评估表型和机制变化。
IS直接损害内皮依赖性血管舒张和内皮细胞迁移。机制研究显示，活性氧相关标志物的产生增加、内皮型一氧化氮合酶减少以及基质金属蛋白酶组织抑制剂1（TIMP1）的蛋白表达增加。IS还增加血管生成素-2和肿瘤坏死因子α基因表达，并促进转化生长因子β受体丰度增加。抑制ASK1至少部分通过降低TIMP1蛋白表达改善了氧化应激标志物的增加，促进了自分泌白细胞介素8促血管生成信号传导并减少了抗血管生成反应。
抑制ASK1可减轻IS受损的血管舒张和内皮细胞迁移。因此，ASK1是减轻尿毒症毒素诱导的血管系统损伤的一个可行的细胞内靶点。
