TY - JOUR
T1 - Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis
AU - Wu, Yanqing
AU - Reece, E. Albert
AU - Zhong, Jianxiang
AU - Dong, Daoyin
AU - Shen, Wei Bin
AU - Harman, Christopher R.
AU - Yang, Peixin
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Background Maternal type 1 and 2 diabetes mellitus are strongly associated with high rates of severe structural birth defects, including congenital heart defects. Studies in type 1 diabetic embryopathy animal models have demonstrated that cellular stress-induced apoptosis mediates the teratogenicity of maternal diabetes leading to congenital heart defect formation. However, the mechanisms underlying maternal type 2 diabetes mellitus–induced congenital heart defects remain largely unknown. Objective We aim to determine whether oxidative stress, endoplasmic reticulum stress, and excessive apoptosis are the intracellular molecular mechanisms underlying maternal type 2 diabetes mellitus–induced congenital heart defects. Study Design A mouse model of maternal type 2 diabetes mellitus was established by feeding female mice a high-fat diet (60% fat). After 15 weeks on the high-fat diet, the mice showed characteristics of maternal type 2 diabetes mellitus. Control dams were either fed a normal diet (10% fat) or the high-fat diet during pregnancy only. Female mice from the high-fat diet group and the 2 control groups were mated with male mice that were fed a normal diet. At E12.5, embryonic hearts were harvested to determine the levels of lipid peroxides and superoxide, endoplasmic reticulum stress markers, cleaved caspase 3 and 8, and apoptosis. E17.5 embryonic hearts were harvested for the detection of congenital heart defect formation using India ink vessel patterning and histological examination. Results Maternal type 2 diabetes mellitus significantly induced ventricular septal defects and persistent truncus arteriosus in the developing heart, along with increasing oxidative stress markers, including superoxide and lipid peroxidation; endoplasmic reticulum stress markers, including protein levels of phosphorylated-protein kinase RNA-like endoplasmic reticulum kinase, phosphorylated-IRE1α, phosphorylated-eIF2α, C/EBP homologous protein, and binding immunoglobulin protein; endoplasmic reticulum chaperone gene expression; and XBP1 messenger RNA splicing, as well as increased cleaved caspase 3 and 8 in embryonic hearts. Furthermore, maternal type 2 diabetes mellitus triggered excessive apoptosis in ventricular myocardium, endocardial cushion, and outflow tract of the embryonic heart. Conclusion Similar to those observations in type 1 diabetic embryopathy, maternal type 2 diabetes mellitus causes heart defects in the developing embryo manifested with oxidative stress, endoplasmic reticulum stress, and excessive apoptosis in heart cells.
AB - Background Maternal type 1 and 2 diabetes mellitus are strongly associated with high rates of severe structural birth defects, including congenital heart defects. Studies in type 1 diabetic embryopathy animal models have demonstrated that cellular stress-induced apoptosis mediates the teratogenicity of maternal diabetes leading to congenital heart defect formation. However, the mechanisms underlying maternal type 2 diabetes mellitus–induced congenital heart defects remain largely unknown. Objective We aim to determine whether oxidative stress, endoplasmic reticulum stress, and excessive apoptosis are the intracellular molecular mechanisms underlying maternal type 2 diabetes mellitus–induced congenital heart defects. Study Design A mouse model of maternal type 2 diabetes mellitus was established by feeding female mice a high-fat diet (60% fat). After 15 weeks on the high-fat diet, the mice showed characteristics of maternal type 2 diabetes mellitus. Control dams were either fed a normal diet (10% fat) or the high-fat diet during pregnancy only. Female mice from the high-fat diet group and the 2 control groups were mated with male mice that were fed a normal diet. At E12.5, embryonic hearts were harvested to determine the levels of lipid peroxides and superoxide, endoplasmic reticulum stress markers, cleaved caspase 3 and 8, and apoptosis. E17.5 embryonic hearts were harvested for the detection of congenital heart defect formation using India ink vessel patterning and histological examination. Results Maternal type 2 diabetes mellitus significantly induced ventricular septal defects and persistent truncus arteriosus in the developing heart, along with increasing oxidative stress markers, including superoxide and lipid peroxidation; endoplasmic reticulum stress markers, including protein levels of phosphorylated-protein kinase RNA-like endoplasmic reticulum kinase, phosphorylated-IRE1α, phosphorylated-eIF2α, C/EBP homologous protein, and binding immunoglobulin protein; endoplasmic reticulum chaperone gene expression; and XBP1 messenger RNA splicing, as well as increased cleaved caspase 3 and 8 in embryonic hearts. Furthermore, maternal type 2 diabetes mellitus triggered excessive apoptosis in ventricular myocardium, endocardial cushion, and outflow tract of the embryonic heart. Conclusion Similar to those observations in type 1 diabetic embryopathy, maternal type 2 diabetes mellitus causes heart defects in the developing embryo manifested with oxidative stress, endoplasmic reticulum stress, and excessive apoptosis in heart cells.
KW - apoptosis
KW - endoplasmic reticulum stress
KW - heart defects
KW - oxidative stress
KW - type 2 diabetes mellitus
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U2 - 10.1016/j.ajog.2016.03.036
DO - 10.1016/j.ajog.2016.03.036
M3 - Article
C2 - 27038779
AN - SCOPUS:84964844960
VL - 215
SP - 366.e1-366.e10
JO - American Journal of Obstetrics and Gynecology
JF - American Journal of Obstetrics and Gynecology
SN - 0002-9378
IS - 3
ER -