2. Academic Validation
  3. aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2

aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2

  • Redox Biol. 2021 Feb:39:101811. doi: 10.1016/j.redox.2020.101811.
Jia Sun 1,  Xiaozhong Huang 2,  Chao Niu 3,  Xuejiao Wang 4,  Wanqian Li 1,  Mengxue Liu 4,  Ying Wang 5,  Shuai Huang 6,  Xixi Chen 7,  Xiaokun Li 1,  Yang Wang 8,  Litai Jin 9,  Jian Xiao 10,  Weitao Cong 11
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
  • 2 Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, PR China.
  • 3 Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, PR China.
  • 4 Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, 325000, China.
  • 5 Department of Pharmacy, Jinhua Women & Children Health Hospital, Jinhua, PR China.
  • 6 Zhejiang Provincial Key Laboratory of Interventional Pulmonology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China.
  • 7 Department of Pharmacy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, PR China.
  • 8 Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: yw1867@126.com.
  • 9 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China. Electronic address: jin_litai@126.com.
  • 10 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China. Electronic address: xfxj2000@126.com.
  • 11 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China. Electronic address: cwt97126@126.com.
PMID: 33360774 DOI: 10.1016/j.redox.2020.101811
Abstract

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.

Keywords

Diabetes; Endothelial dysfunction; HXK2; Mitochondrial superoxide; aFGF.

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