Cargando…
aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2
Vascular complications of diabetes are a serious challenge in clinical practice, and effective treatments are an unmet clinical need. Acidic fibroblast growth factor (aFGF) has potent anti-oxidative properties and therefore has become a research focus for the treatment of diabetic vascular complicat...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772795/ https://www.ncbi.nlm.nih.gov/pubmed/33360774 http://dx.doi.org/10.1016/j.redox.2020.101811 |
_version_ | 1783629943243014144 |
---|---|
author | Sun, Jia Huang, Xiaozhong Niu, Chao Wang, Xuejiao Li, Wanqian Liu, Mengxue Wang, Ying Huang, Shuai Chen, Xixi Li, Xiaokun Wang, Yang Jin, Litai Xiao, Jian Cong, Weitao |
author_facet | Sun, Jia Huang, Xiaozhong Niu, Chao Wang, Xuejiao Li, Wanqian Liu, Mengxue Wang, Ying Huang, Shuai Chen, Xixi Li, Xiaokun Wang, Yang Jin, Litai Xiao, Jian Cong, Weitao |
author_sort | Sun, Jia |
collection | PubMed |
description | Vascular complications of diabetes are a serious challenge in clinical practice, and effective treatments are an unmet clinical need. Acidic fibroblast growth factor (aFGF) has potent anti-oxidative properties and therefore has become a research focus for the treatment of diabetic vascular complications. However, the specific mechanisms by which aFGF regulates these processes remain unclear. The purpose of this study was to investigate whether aFGF alleviates diabetic endothelial dysfunction by suppressing mitochondrial oxidative stress. We found that aFGF markedly decreased mitochondrial superoxide generation in both db/db mice and endothelial cells incubated with high glucose (30 mM) plus palmitic acid (PA, 0.1 mM), and restored diabetes-impaired Wnt/β-catenin signaling. Pretreatment with the Wnt/β-catenin signaling inhibitors IWR-1-endo (IWR) and ICG-001 abolished aFGF-mediated attenuation of mitochondrial superoxide generation and endothelial protection. Furthermore, the effects of aFGF on endothelial protection under diabetic conditions were suppressed by c-Myc knockdown. Mechanistically, c-Myc knockdown triggered mitochondrial superoxide generation, which was related to decreased expression and subsequent impaired mitochondrial localization of hexokinase 2 (HXK2). The role of HXK2 in aFGF-mediated attenuation of mitochondrial superoxide levels and EC protection was further confirmed by si-Hxk2 and a cell-permeable form of hexokinase II VDAC binding domain (HXK2VBD) peptide, which inhibits mitochondrial localization of HXK2. Taken together, these findings suggest that the endothelial protective effect of aFGF under diabetic conditions could be partly attributed to its role in suppressing mitochondrial superoxide generation via HXK2, which is mediated by the Wnt/β-catenin/c-Myc axis. |
format | Online Article Text |
id | pubmed-7772795 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-77727952020-12-31 aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2 Sun, Jia Huang, Xiaozhong Niu, Chao Wang, Xuejiao Li, Wanqian Liu, Mengxue Wang, Ying Huang, Shuai Chen, Xixi Li, Xiaokun Wang, Yang Jin, Litai Xiao, Jian Cong, Weitao Redox Biol Research Paper Vascular complications of diabetes are a serious challenge in clinical practice, and effective treatments are an unmet clinical need. Acidic fibroblast growth factor (aFGF) has potent anti-oxidative properties and therefore has become a research focus for the treatment of diabetic vascular complications. However, the specific mechanisms by which aFGF regulates these processes remain unclear. The purpose of this study was to investigate whether aFGF alleviates diabetic endothelial dysfunction by suppressing mitochondrial oxidative stress. We found that aFGF markedly decreased mitochondrial superoxide generation in both db/db mice and endothelial cells incubated with high glucose (30 mM) plus palmitic acid (PA, 0.1 mM), and restored diabetes-impaired Wnt/β-catenin signaling. Pretreatment with the Wnt/β-catenin signaling inhibitors IWR-1-endo (IWR) and ICG-001 abolished aFGF-mediated attenuation of mitochondrial superoxide generation and endothelial protection. Furthermore, the effects of aFGF on endothelial protection under diabetic conditions were suppressed by c-Myc knockdown. Mechanistically, c-Myc knockdown triggered mitochondrial superoxide generation, which was related to decreased expression and subsequent impaired mitochondrial localization of hexokinase 2 (HXK2). The role of HXK2 in aFGF-mediated attenuation of mitochondrial superoxide levels and EC protection was further confirmed by si-Hxk2 and a cell-permeable form of hexokinase II VDAC binding domain (HXK2VBD) peptide, which inhibits mitochondrial localization of HXK2. Taken together, these findings suggest that the endothelial protective effect of aFGF under diabetic conditions could be partly attributed to its role in suppressing mitochondrial superoxide generation via HXK2, which is mediated by the Wnt/β-catenin/c-Myc axis. Elsevier 2020-12-19 /pmc/articles/PMC7772795/ /pubmed/33360774 http://dx.doi.org/10.1016/j.redox.2020.101811 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Sun, Jia Huang, Xiaozhong Niu, Chao Wang, Xuejiao Li, Wanqian Liu, Mengxue Wang, Ying Huang, Shuai Chen, Xixi Li, Xiaokun Wang, Yang Jin, Litai Xiao, Jian Cong, Weitao aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2 |
title | aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2 |
title_full | aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2 |
title_fullStr | aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2 |
title_full_unstemmed | aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2 |
title_short | aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2 |
title_sort | afgf alleviates diabetic endothelial dysfunction by decreasing oxidative stress via wnt/β-catenin-mediated upregulation of hxk2 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772795/ https://www.ncbi.nlm.nih.gov/pubmed/33360774 http://dx.doi.org/10.1016/j.redox.2020.101811 |
work_keys_str_mv | AT sunjia afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT huangxiaozhong afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT niuchao afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT wangxuejiao afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT liwanqian afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT liumengxue afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT wangying afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT huangshuai afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT chenxixi afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT lixiaokun afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT wangyang afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT jinlitai afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT xiaojian afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 AT congweitao afgfalleviatesdiabeticendothelialdysfunctionbydecreasingoxidativestressviawntbcateninmediatedupregulationofhxk2 |