Simvastatin attenuates TNF‑α‑induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1

Int J Mol Med. 2014 Jul;34(1):177-82. doi: 10.3892/ijmm.2014.1740. Epub 2014 Apr 9.


Endothelial progenitor cells (EPCs) originate from the bone marrow and can be classified as either early or late EPCs. The focus of this study was on late EPCs, as they play an important role in angiogenesis and vascular proliferation. Evidence suggests that inflammatory and oxidative changes can increase EPC apoptosis. Of note, tumor necrosis factor-α (TNF-α) is a contributing risk factor to the development of atherosclerosis and plays a key role as both an inflammatory mediator and an inducer of apoptosis in endothelial cells. Additionally, a member of the sirtuin family, silent information regulator type-1 (SIRT1), promotes cell survival by repressing p53- and non-p53-dependent apoptosis in response to DNA damage and oxidative stress. Statins have also been shown to play a key role in the prevention of endothelial apoptosis and senescence via their lipid-lowering and anti-inflammatory actions. However, there is little evidence that statins themselves attenuate EPC apoptosis induced by TNF-α. The aim of this study was to demonstrate the effectiveness of one of the most commonly used statins, simvastatin, on decreasing TNF-α-induced apoptosis in EPCs. The results indicated that SIRT1 protein expression was decreased by TNF-α in a time- and dose-dependent manner and that while TNF-α caused a marked increase in the percentage of apoptotic EPCs, application of simvastatin decreased this percentage. A high concentration of simvastatin promoted the expression of SIRT1 and increased the proliferation of EPCs. In conclusion, findings of this study showed that simvastatin is crucial in counteracting the TNF-α-induced apoptosis of EPCs and that this protection may involve the actions of SIRT1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelial Progenitor Cells / cytology
  • Endothelial Progenitor Cells / drug effects*
  • Endothelial Progenitor Cells / metabolism
  • Fetal Blood / cytology
  • Fetal Blood / metabolism
  • Humans
  • Signal Transduction
  • Simvastatin / pharmacology*
  • Sirtuin 1 / genetics*
  • Sirtuin 1 / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology
  • Up-Regulation


  • Anticholesteremic Agents
  • Tumor Necrosis Factor-alpha
  • Simvastatin
  • SIRT1 protein, human
  • Sirtuin 1