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TWEAK/Fn14 promotes oxidative stress through AMPK/PGC­1α/MnSOD signaling pathway in endothelial cells.
Mol Med Rep ; 17(1): 1998-2004, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29257217
ABSTRACT
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) contributes to dysfunction of endothelial cells via its receptor, Fn14. However, its role in the production of reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS) and the subsequent decrease in nitric oxide (NO) in endothelial cells remains unclear. In this study, the effect of TWEAK/Fn14 on generation of ROS, mtROS and NO in endothelial cells and its potential mechanism was investigated. Human umbilical vein endothelial cells (HUVECs) were treated with TWEAK with Fn14 small interfering (si)RNA or negative control RNA. It was demonstrated that TWEAK induced the production of ROS and mtROS in HUVECs, which were detected by fluorescent microscope, and flow cytometry. In addition, TWEAK decreased the generation of NO as indicated using the Nitric Oxide Assay kit. Furthermore, TWEAK aggravated mtDNA damage as measured by quantitative polymerase chain reaction analysis. Inhibition of Fn14 by Fn14 siRNA decreased TWEAK­induced ROS and mtROS production, as well as mtDNA damage, while it increased the production of NO in endothelial cells. In addition, TWEAK inhibited the expression of active AMP­activated protein kinase (AMPK) and its downstream protein peroxisome proliferator­activated receptor­Î³ coactivator-1α (PGC­1α) and manganese superoxide dismutase (MnSOD). Notably, Fn14 siRNA enhanced the expression of the aforementioned proteins. Taken together, TWEAK/Fn14 contributes to endothelial dysfunction through modulation of ROS and mtROS. In addition, the underlying mechanism is implicated in the AMPK/PGC­1α/MnSOD signaling pathway.
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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Estresse Oxidativo / Células Endoteliais / Proteínas Quinases Ativadas por AMP / Citocina TWEAK / Receptor de TWEAK Limite: Humanos Idioma: Inglês Revista: Mol Med Rep Ano de publicação: 2018 Tipo de documento: Artigo