SIRT1 activation promotes angiogenesis in diabetic wounds by protecting endothelial cells against oxidative stress

Arch Biochem Biophys. 2019 Jan;661:117-124. doi: 10.1016/j.abb.2018.11.016. Epub 2018 Nov 17.

Abstract

Objective: Chronic wounds are a devastating complication of diabetes and can lead to amputations or even death. Current medical therapies are insufficient to accelerate its repair. The objective of this study was to explore the role of Sirtuin1 (SIRT1) in diabetic wounds.

Methods and materials: Perilesional skin tissue samples from diabetic ulcers and normoglycemic trauma wounds were used to detect SIRT1 expression and oxidative stress levels. In a diabetic mouse model, SIRT1 was pharmacologically activated to attenuate angiogenesis and accelerate wound closure. Finally, in vitro experiments were performed to elucidate some of the mechanisms by which SIRT1 activation promotes angiogenesis in diabetic wound healing.

Results: We found that skin tissue from diabetes patients showed lower expression of SIRT1 and severe oxidative stress. Decreased SIRT1 expression was observed in skin tissue from streptozocin (STZ)-induced diabetic mice and was associated with impaired wound healing. In addition, the wounds of STZ-induced diabetic mice treated with SRT1720 (a specific SIRT1 activator) demonstrated locally improved wound healing and angiogenesis. In the in vitro experiment, similar results were observed. Under hyperglycemia conditions, human umbilical vein endothelial cells (HUVECs) showed lower expression of SIRT1 and higher levels of reactive oxygen species (ROS) production. Furthermore, the migration, proliferation and in vitro tube formation ability of HUVECs were impaired under hyperglycemia conditions, and SRT1720 treatment rescued these impairments and decreased ROS production in HUVECs.

Conclusions: This study provides experimental evidence that SIRT1 activation could improve angiogenesis in wounds in vitro and in vivo and that sirtuin1 activation accelerates wound healing in diabetic mice by promoting angiogenesis. These positive therapeutic effects may be mediated by protecting vascular endothelial cells from oxidative stress injury. This study suggested that SIRT1 may serve as a potentially important and potent therapeutic target for treating diabetic ulcers.

Keywords: Angiogenesis; Diabetes; Oxidative stress; Sirtuin1; Wound healing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetic Angiopathies / enzymology*
  • Diabetic Angiopathies / pathology
  • Female
  • Human Umbilical Vein Endothelial Cells / enzymology*
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Male
  • Mice
  • Neovascularization, Pathologic / enzymology*
  • Neovascularization, Pathologic / pathology
  • Oxidative Stress*
  • Sirtuin 1 / metabolism*
  • Wounds and Injuries / enzymology*
  • Wounds and Injuries / pathology

Substances

  • SIRT1 protein, human
  • Sirtuin 1