Antioxidative and Angiogenesis-Promoting Effects of Tetrahedral Framework Nucleic Acids in Diabetic Wound Healing with Activation of the Akt/Nrf2/HO-1 Pathway

ACS Appl Mater Interfaces. 2020 Mar 11;12(10):11397-11408. doi: 10.1021/acsami.0c00874. Epub 2020 Feb 28.

Abstract

Currently available strategies show limited effects in preventing morbidity and disability from chronic diabetic wounds. Ideal vascularization is indispensable for better restoration and prognosis of diabetic wounds. This study aims to investigate the role of tetrahedral framework nucleic acids (tFNAs) in the process of angiogenesis during diabetic wound healing and the underlying mechanism. The in vitro results showed that tFNAs treatment enhanced the formation of a vessel-like structure that was inhibited by advanced glycation end products (AGEs). Positive variations were detected in aspects of cell viability, migratory ability, nitric oxide (NO) levels, and vascular endothelial growth factor-A (VEGF-A) expression. In addition, high reactive oxygen species (ROS) levels and gene expressions relevant to oxidative damage and inflammation in diabetic human umbilical vein endothelial cells (HUVECs) were attenuated by tFNAs. As for the underlying mechanism, the p-Akt/total Akt ratio, nuclear factor erythroid 2-related factor 2 (Nrf2) levels, and heme oxygenase-1 (HO-1) levels were higher in diabetic HUVECs treated with tFNAs. In vivo experiments showed that tFNAs facilitated diabetic wound healing by accelerating vascularization, epithelialization, collagen deposition, and collagen alignment. In conclusion, tFNAs could protect endothelial cell function, reduce inflammation, and impede oxidative damage through their antioxidant activity via the Akt/Nrf2/HO-1 signaling pathway. The application of tFNAs may pave the way for better healing of diabetic wounds.

Keywords: AGEs; DNA nanostructure; angiogenesis; diabetic wound healing; oxidative damage.

MeSH terms

  • Angiogenesis Inducing Agents / chemistry
  • Angiogenesis Inducing Agents / pharmacology*
  • Animals
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Cells, Cultured
  • Diabetic Foot / metabolism
  • Disease Models, Animal
  • Glycation End Products, Advanced / metabolism
  • Heme Oxygenase-1 / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • NF-E2-Related Factor 2 / metabolism
  • Nanostructures / chemistry
  • Nucleic Acids / chemistry
  • Nucleic Acids / pharmacology*
  • Oxidative Stress / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Wound Healing / drug effects*

Substances

  • Angiogenesis Inducing Agents
  • Antioxidants
  • Glycation End Products, Advanced
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nucleic Acids
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Proto-Oncogene Proteins c-akt