Maternal diabetes up-regulates NOX2 and enhances myocardial ischaemia/reperfusion injury in adult offspring
Open accessAbstract
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.
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Significant increases in ischemia-induced cardiac infarction have been reported in adult male and female offspring of STZ-induced diabetes dams.
“Significant increases in ischemia-induced cardiac infarction have also been reported in adult male and female offspring of STZ-induced diabetes dams [120,121].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [121]
The Results section reports a larger infarct size after ischaemia/reperfusion in adult offspring of STZ-treated diabetic mothers. However, the Methods section and Figure 2 caption specify that the mice tested were male; this paper does not support the claim about female offspring. Page numbers are not available in our copy. (LLM, conf=0.93)
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- Authors
- Zhang, L., Wang, X., Wu, Y., Lu, X., Chidiac, P., Wang, G., & Feng, Q.
- Affiliations
- Western University (CA)
- Tongji Hospital (CN)
- Corresponding author
- Wang, Guoping
- Feng, Qingping
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2018-01-29
- Volume
- 22
- Issue
- 4
- Pages
- 2200-2209
- ISSN
- 1582-1838 (ISSN-L)
- 1582-4934
- PMC
- PMC5867143
- OpenAlex
- W2792882867
- Cited by
- 17
- References
- 47
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 2
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Scholarship@Western (Western University) (submittedVersion)
- Funders
- Canadian Institutes of Health Research (MOP‐119600, MOP‐142383)
- National Natural Science Foundation of China (#81270176, #81570254)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- maternal diabetes, myocardial ischemia-reperfusion injury, NADPH oxidase NOX2, reactive oxygen species, cardiomyocyte apoptosis, infarct size, high glucose, apocynin, rapamycin, streptozotocin-induced diabetes, offspring of diabetic mothers
- MeSH terms
- NADPH Oxidase 2, Aging, Animals, Animals, Newborn, Cells, Cultured, Diabetes Mellitus, Experimental, Female, Glucose, Mice, Inbred C57BL, Pregnancy, Signal Transduction, Myocardial Reperfusion Injury, Up-Regulation, Diabetes, Gestational, Apoptosis, Reactive Oxygen Species, Myocytes, Cardiac, Vascular Endothelial Growth Factor A, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases
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