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Maternal Exercise Rescues Congenital Heart Defects Induced by Pregestational Diabetes

The following abstract was presented as part of London Health Research Day 2017.
 

Research Areas: Fetal, family development; Prevention of diseases and health conditions and promotion of well-being
First Author: Tana Saiyin
Supervisor(s): Drs. Qingping Feng and Douglas Jones

Introduction:
The prevalence of diabetes is growing at epidemic proportions, with 1 in 10 adults estimated to have the disease by the year 2040. From a developmental standpoint, this is concerning because women with diabetes have a 4 times increased risk of producing offspring with congenital heart defects (CHDs). A hyperglycemic gestational environment promotes the production of reactive oxygen species (ROS), which are detrimental to proteins involved in normal heart development. One such protein is endothelial nitric oxide synthase (eNOS), an enzyme that plays a critical role in cardiogenesis. Under conditions of oxidative stress, eNOS becomes undimerized or “uncoupled”, and produces superoxide rather than nitric oxide. It has been demonstrated that recoupling eNOS can counteract the detrimental effects of pregestational diabetes on heart development. Remarkably, a recent study showed that maternal voluntary exercise during pregnancy could reduce the age-related risk of producing offspring with CHDs. Exercise has the ability to upregulate eNOS expression and activity in adult cardiovascular tissues. However, whether maternal exercise can regulate fetal eNOS and have the potential to rescue CHDs induced by pregestational diabetes has yet to be studied.

Hypothesis:
Maternal voluntary exercise during pregnancy will decrease the incidence of CHDs induced by pregestational diabetes. Objective 1: Test whether exercise in pregnant dams with pregestational diabetes can lower the incidence of CHDs in the offspring. Objective 2: Analyze the effects of exercise and pregestational diabetes on cell proliferation and gene expression in embryonic hearts. Objective 3: Determine if maternal voluntary exercise can decrease ROS and restore embryonic eNOS expression and activity.

Materials and Methods:
Two month old C57BL/6 females were IP injected with saline or 50mg/kg STZ for 5 consecutive days. Mice with blood glucose >11 mmol/L were considered diabetic, bred with WT males, and placed in a cage with or without a running. Hearts were collected at E18.5 to diagnose CHDs and coronary artery defects via immunostaining and 3D reconstruction with AMIRA software. Embryonic hearts at E12.5 were collected to examine proliferation, oxidative stress, and mRNA expression of eNOS and developmental genes. Western blots of E14.5 hearts were used to analyze phospho-eNOS to total eNOS expression.

Results:
Incidence of CHDs in offspring of diabetic mice was significantly reduced by maternal exercise from 63 to 31%. Fetal hearts showed improved aortic and pulmonary valve remodeling compared to the non-exercised diabetic group. Defects in coronary artery volume as well as capillary density were also rescued with exercise. Myocardial proliferation at E12.5 was significantly decreased with pregestational diabetes but recovered with maternal exercise. Furthermore, embryonic cardiac gene expression of eNOS, as well as cardiogenesis transcription factors Nkx2.5 and Gata4 were rescued by maternal exercise. Preliminary results show reduced levels of ROS in embryonic hearts of offspring from diabetic mice that exercised.

Discussion and Conclusions:
For the first time, we demonstrate that maternal exercise is effective in mitigating pregestational diabetes induced defects in cardiovascular development. These findings provide evidence that exercise may be a feasible intervention to counteract the effects of diabetes-induced CHDs in the population.