Endoplasmic reticulum stress in maternal diabetes-induced cardiac malformations during critical cardiogenesis period.

BACKGROUND: Cardiac abnormalities, including atrioventricular (AV) septal defects (AVSDs), are the most common birth defects in diabetic embryopathy. The AV septum is derived from the endocardial cushions, which undergo development and remodeling during septation. The impact of maternal diabetes on these processes needs to be identified. Maternal diabetes disturbs the function of the endoplasmic reticulum (ER). The role of ER stress in cardiac malformation remains to be delineated to gain information for developing therapy.

METHODS: Female mice were induced diabetic via intravenous injection of streptozotocin. Pregnant mice were made hyperglycemic at desired embryonic (E) days. AVSDs were examined histologically at E15.5. ER stress-associated factors were examined and quantified using immunohistochemical and immunoblot assays at E10.5. The role of ER stress in endocardial cell migration was investigated by treating endocardial cushion explants that were cultured in high glucose with an organic chaperone molecule, sodium 4-phenylbutyrate.

RESULTS: The rate of AVSDs in the embryos that were exposed to maternal hyperglycemia during the period of endocardial cushion development was significantly higher than that in those during endocardial cushion remodeling. ER stress was increased in the hearts. Amelioration of ER stress restored endocardial cell migration under hyperglycemic conditions.

CONCLUSIONS: The development, rather than remodeling, of the endocardial cushions is the cardiomorphogenic process that is susceptible to the insult of maternal hyperglycemia in the formation of AVSDs. Maternal diabetes increases ER stress in the developing heart. ER stress plays an essential role in mediating the effect of hyperglycemia on endocardial cell migration.