High glucose induces vascular endothelial growth factor production in human synovial fibroblasts through reactive oxygen species generation |
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Authors: | Chun-Hao Tsai Yi-Chun Chiang Hsien-Te Chen Po-Hao Huang Horng-Chaung Hsu Chih-Hsin Tang |
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Affiliation: | 1. Department of Orthopaedic Surgery, China Medical University Hospital, Taichung, Taiwan;2. Department of Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan;3. Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan;4. Department of Rheumatoloy, China Medical University Hospital, Taichung, Taiwan;5. Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan;6. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan |
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Abstract: | BackgroundDiabetes is an independent risk factor of osteoarthritis (OA). Angiogenesis is essential for the progression of OA. Here, we investigated the intracellular signaling pathways involved in high glucose (HG)-induced vascular endothelial growth factor (VEGF) expression in human synovial fibroblast cells.MethodsHG-mediated VEGF expression was assessed with qPCR and ELISA. The mechanisms of action of HG in different signaling pathways were studied using Western blotting. Knockdown of proteins was achieved by transfection with siRNA. Chromatin immunoprecipitation assays were used to study in vivo binding of c-Jun to the VEGF promoter.ResultsStimulation of OA synovial fibroblasts (OASF) with HG induced concentration- and time-dependent increases in VEGF expression. Treatment of OASF with HG increased reactive oxygen species (ROS) generation. Pretreatment with NADPH oxidase inhibitor (APO or DPI), ROS scavenger (NAC), PI3K inhibitor (Ly294002 or wortmannin), Akt inhibitor, or AP-1 inhibitor (curcumin or tanshinone IIA) blocked the HG-induced VEGF production. HG also increased PI3K and Akt activation. Treatment of OASF with HG increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the VEGF promoter.ConclusionsOur results suggest that the HG increases VEGF expression in human synovial fibroblasts via the ROS, PI3K, Akt, c-Jun and AP-1 signaling pathway.General significanceWe link high glucose on VEGF expression in osteoarthritis. |
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Keywords: | Glucose VEGF ROS OA |
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