Transcription box‑3 protects human umbilical vein endothelial cells in a high‑glucose environment through sirtuin 1/AKT signaling

Mol Med Rep. 2020 Aug;22(2):1145-1154. doi: 10.3892/mmr.2020.11237. Epub 2020 Jun 15.

Abstract

The increasing burden of diabetes in low and middle‑income countries is attributable to both genetic and epigenetic factors. Environmental‑ and lifestyle‑associated changes are also considered to be important contributors to this disease. The resultant co‑morbidities arising from micro‑and macrovascular changes in diabetes are difficult to manage and are an economic burden. However, very little is known about the molecular mechanisms that drive this phenotype. The present study aimed to investigate the role of sirtuin 1 (SIRT1)‑ and transcription box‑3 (TBX‑3)‑mediated regulation of endothelial dysfunction, given the significance of SIRT1 in glucose metabolism and the role of TBX‑3 in the maintenance of cellular proliferation, senescence and apoptosis. Following the recruitment of adult patients with and without diabetes, both SIRT1 and TBX‑3 expression was confirmed to be present in the sera of the patients with diabetes and the patients without diabetes; however, both SIRT1 and TBX‑3 expression levels were higher in the sera of the patients with diabetes. Human umbilical vein endothelial cells (HUVECs) were further used for in vitro studies. Using TBX‑3 and SIRT1 knockdown models, the cellular responses to proliferation, migration, invasion and tube formation were investigated using an MTS, cell cycle analysis, wound healing, Transwell and tube formation assay, respectively. Western blotting was also used to determine the downstream signaling pathways involved. The genetic knockdown of TBX‑3 in hyperglycemic conditions significantly decreased the cellular proliferation, migration, invasion and angiogenesis of HUVECs. It was subsequently identified that TBX‑3 mediated its effects through the activation of AKT and vascular endothelial growth factor (VEGF) signaling. However, the genetic knockdown of SIRT1 in the presence of TBX‑3 overexpression and glucose failed to activate the AKT and VEGF signaling pathways. In conclusion, the results of the present study suggested that SIRT1 may positively regulate TBX‑3 in endothelial cells, therefore, SIRT1 and/or TBX‑3 may serve as potential novel biomarkers for disease progression.

Keywords: transcription box-3; sirtuin 1; angiogenesis; migration; invasion; diabetes.

MeSH terms

  • Adult
  • Biomarkers / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Glucose
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Male
  • Middle Aged
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Sirtuin 1 / physiology*
  • T-Box Domain Proteins / physiology*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Biomarkers
  • T-Box Domain Proteins
  • TBX3 protein, human
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Proto-Oncogene Proteins c-akt
  • SIRT1 protein, human
  • Sirtuin 1
  • Glucose