Maternal diabetes up-regulates NOX2 and enhances myocardial ischaemia/reperfusion injury in adult offspring

J Cell Mol Med. 2018 Apr;22(4):2200-2209. doi: 10.1111/jcmm.13500. Epub 2018 Jan 29.


Offspring of diabetic mothers are at risk of cardiovascular diseases in adulthood. However, the underlying molecular mechanisms are not clear. We hypothesize that prenatal exposure to maternal diabetes up-regulates myocardial NOX2 expression and enhances ischaemia/reperfusion (I/R) injury in the adult offspring. Maternal diabetes was induced in C57BL/6 mice by streptozotocin. Glucose-tolerant adult offspring of diabetic mothers and normal controls were subjected to myocardial I/R injury. Vascular endothelial growth factor (VEGF) expression, ROS generation, myocardial apoptosis and infarct size were assessed. The VEGF-Akt (protein kinase B)-mammalian target of rapamycin (mTOR)-NOX2 signalling pathway was also studied in cultured cardiomyocytes in response to high glucose level. In the hearts of adult offspring from diabetic mothers, increases were observed in VEGF expression, NOX2 protein levels and both Akt and mTOR phosphorylation levels as compared to the offspring of control mothers. After I/R, ROS generation, myocardial apoptosis and infarct size were all significantly higher in the offspring of diabetic mothers relative to offspring of control mothers, and these differences were diminished by in vivo treatment with the NADPH oxidase inhibitor apocynin. In cultured cardiomyocytes, high glucose increased mTOR phosphorylation, which was inhibited by the PI3 kinase inhibitor LY294002. Notably, high glucose-induced NOX2 protein expression and ROS production were inhibited by rapamycin. In conclusion, maternal diabetes promotes VEGF-Akt-mTOR-NOX2 signalling and enhances myocardial I/R injury in the adult offspring. Increased ROS production from NOX2 is a possible molecular mechanism responsible for developmental origins of cardiovascular disease in offspring of diabetic mothers.

Keywords: NOX2; developmental origins of health and disease; mTOR; maternal diabetes; myocardial ischaemia and reperfusion injury; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology*
  • Animals
  • Animals, Newborn
  • Apoptosis
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetes, Gestational / pathology*
  • Female
  • Glucose / toxicity
  • Mice, Inbred C57BL
  • Myocardial Reperfusion Injury / pathology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • NADPH Oxidase 2 / metabolism*
  • Pregnancy
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Up-Regulation*
  • Vascular Endothelial Growth Factor A / metabolism


  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • NADPH Oxidase 2
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Glucose