2. Academic Validation
  3. Downregulation of VEGFA accelerates AGEs-mediated nucleus pulposus degeneration through inhibiting protective mitophagy in high glucose environments

Downregulation of VEGFA accelerates AGEs-mediated nucleus pulposus degeneration through inhibiting protective mitophagy in high glucose environments

  • Int J Biol Macromol. 2024 Feb 5;262(Pt 1):129950. doi: 10.1016/j.ijbiomac.2024.129950.
Depeng Wu 1,  Weijun Huang 1,  Junbin Zhang 2,  Lei He 1,  Siyu Chen 3,  Sihan Zhu 4,  Yuan Sang 2,  Kaihua Liu 2,  Gang Hou 2,  Biying Chen 2,  Yichun Xu 2,  Bin Liu 5,  Hui Yao 6
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR China.
  • 2 Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China.
  • 3 Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, PR China.
  • 4 University Hospital, LMU Munich, 81377 Munich, Germany.
  • 5 Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR China. Electronic address: liubin6@mail.sysu.edu.cn.
  • 6 Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China. Electronic address: yaohui3@mail.sysu.edu.cn.
PMID: 38320636 DOI: 10.1016/j.ijbiomac.2024.129950
Abstract

Intervertebral disc degeneration (IVDD) contributes largely to low back pain. Recent studies have highlighted the exacerbating role of diabetes mellitus (DM) in IVDD, mainly due to the influence of hyperglycemia (HG) or the accumulation of advanced glycation end products (AGEs). Vascular endothelial growth factor A (VEGFA) newly assumed a distinct impact in nonvascular tissues through Mitophagy regulation. However, the combined actions of HG and AGEs on IVDD and the involved role of VEGFA remain unclear. We confirmed the potential relation between VEGFA and DM through bioinformatics and biological specimen detection. Then we observed that AGEs induced nucleus pulposus (NP) cell degeneration by upregulating cellular Reactive Oxygen Species (ROS), and HG further aggravated ROS level through breaking AGEs-induced protective Mitophagy. Furthermore, this adverse effect could be strengthened by VEGFA knockdown. Importantly, we identified that the regulation of VEGFA and Mitophagy were vital mechanisms in AGEs-HG-induced NP cell degeneration through Parkin/Akt/mTOR and AMPK/mTOR pathway. Additionally, VEGFA overexpression through local injection with lentivirus carrying VEGFA plasmids significantly alleviated NP degeneration and IVDD in STZ-induced diabetes and puncture rat models. In conclusion, the findings first confirmed that VEGFA protects against AGEs-HG-induced IVDD, which may represent a therapeutic strategy for DM-related IVDD.

Keywords

Diabetes mellitus; Mitochondrial dysfunction; Mitophagy; Nucleus pulposus degeneration; Vascular endothelial growth factor A.

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