Oscillating high glucose enhances oxidative stress and apoptosis in human coronary artery endothelial cells

J Endocrinol Invest. 2014 Jul;37(7):645-51. doi: 10.1007/s40618-014-0086-5. Epub 2014 May 24.


Purpose: To investigate the toxic effect of oscillating high glucose (OHG) versus persistent high glucose (PHG) in inducing oxidative stress and cellular apoptosis in human coronary artery endothelial cells (HCAECs) in vitro.

Methods: HCAECs were incubated for 72 h continuously in normal glucose (5.5 mmol/L glucose), PHG (25 mmol/L glucose), OHG (5.5 mmol and 25 glucose mmol/L alternating every 6 h) and mannitol, respectively. Cellular viability, concentration of oxidative stress biomarkers (MDA and GSH) in the supernatants of cell culture, and intracellular ROS level were quantitated after exposure to different concentrations of glucose for a total 72 h. Apoptosis of HCAECs cultured with various glucose levels was evaluated by annexin V-FITC and PI staining followed by analysis with flow cytometry. The expressions of HO-1 and Nrf2 were measured by RT-qPCR and Western blotting at the end of the experiment.

Results: HCAECs cultured with PHG showed decreased cellular viability compared to those with normal level of glucose (p < 0.05). The decrease was more pronounced under OHG condition (p < 0.05). Cellular oxidative stress was provoked in HCAECs exposed to PHG with marked increased MDA level, reduced GSH concentration and elevated ROS production (p < 0.05). The stress was further amplified in the setting of OHG (p < 0.05). The cellular apoptosis was enhanced by culturing with PHG, and to a greater extent when incubated with OHG. Both expressions of HO-1 and Nrf2 were suppressed in HCAECs in persistent hyperglycemia condition, while the inhibition was more intense in the fluctuating hyperglycemia condition (p < 0.05).

Conclusions: These findings indicate that OHG could be more detrimental to HCAECs than PHG. This is probably due to the enhancement of oxidative stress and cellular apoptosis induced by frequent glucose swings through the inhibition of Nrf2/HO-1 pathway.

MeSH terms

  • Apoptosis / drug effects*
  • Cell Line
  • Cell Survival / drug effects
  • Coronary Vessels / cytology
  • Coronary Vessels / drug effects*
  • Coronary Vessels / metabolism
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Glucose / administration & dosage*
  • Glutathione / metabolism
  • Humans
  • Malondialdehyde / metabolism
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism


  • Reactive Oxygen Species
  • Malondialdehyde
  • Glutathione
  • Glucose