Apoptosis signal-regulating kinase 1 inhibition reverses deleterious indoxyl sulfate-mediated endothelial effects.

Autor: Savira F; 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., Kompa AR; 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., Magaye R; 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., Xiong X; 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., Huang L; 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., Jucker BM; Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA, USA., Willette RN; Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA, USA., Kelly DJ; Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Australia., Wang BH; 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. Electronic address: bing.wang@baker.edu.au.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2021 May 01; Vol. 272, pp. 119267. Date of Electronic Publication: 2021 Feb 22.
DOI: 10.1016/j.lfs.2021.119267
Abstrakt: Aims: 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.
Main Methods: 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.
Key Findings: 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.
Significance: 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.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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