Type 2 diabetes mellitus induces congenital heart defects in murine embryos by increasing oxidative stress, endoplasmic reticulum stress, and apoptosis

Abstract

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.

The increased activity of a transcription factor inhibits autophagy in diabetic embryopathy

“…It has been shown that maternal diabetes induces oxidative stress by enhancing the production of endogenous reactive oxygen species and decreasing cellular antioxidant defense enzyme activity. 8,9,17,25–27 Studies using the transgenic mouse model that overexpresses the antioxidant enzyme, superoxide dismutase 1, have demonstrated that eliminating reactive oxygen species caused by maternal diabetes can effectively resolve cellular stress and proapoptotic signaling. 28–30 In complementary with the previous findings that FoxO3a mediates the proapoptotic effect of maternal diabetes, the present study further discovered that the transcription activity of FoxO3a is essential for cell apoptosis because deletion of the FoxO3a transactivation domain abolished maternal diabetes-induced neuroepithelial cell apoptosis and NTD formation.…”

Pregestational type 2 diabetes mellitus induces cardiac hypertrophy in the murine embryo through cardiac remodeling and fibrosis

“…The animal model described in this study allows deep mechanistic studies; however, it may not faithfully reflect the human conditions. This concern is significantly alleviated because both diabetic animal models and human pregestational diabetes induce a same set of structural birth defects 62, 63, 72, 73, 75–77, 97–99 .…”

Reduction of cellular stress is essential for Fibroblast growth factor 1 treatment for diabetic nephropathy

“…Cellular stress is a component of the development of various kidney diseases . Our mechanism studies have revealed that elevated oxidative stress and ER stress are the causal events for diabetes‐related complications . Oxidative stress is a condition in which generation of reactive oxygen species (ROS) exceeds the capacity of the antioxidant defense system, caused by increased ROS production and impaired antioxidant capacity .…”