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However, the underlying molecular mechanisms are not clear. We hypothesize that prenatal exposure to maternal diabetes up\u2010regulates 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\u2010tolerant 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\u2010Akt (protein kinase B)\u2010mammalian target of rapamycin (mTOR)\u2010NOX2 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 <jats:italic>in\u00a0vivo<\/jats:italic> 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\u2010induced NOX2 protein expression and ROS production were inhibited by rapamycin. In conclusion, maternal diabetes promotes VEGF\u2010Akt\u2010mTOR\u2010NOX2 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.<\/jats:p>","DOI":"10.1111\/jcmm.13500","type":"journal-article","created":{"date-parts":[[2018,1,29]],"date-time":"2018-01-29T22:12:47Z","timestamp":1517263967000},"page":"2200-2209","source":"Crossref","is-referenced-by-count":16,"title":["Maternal diabetes up\u2010regulates NOX2 and enhances myocardial ischaemia\/reperfusion injury in adult offspring"],"prefix":"10.1111","volume":"22","author":[{"given":"Lili","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Pathology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China"},{"name":"Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry University of Western Ontario London Ontario 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