Superoxide Dismutase 1 In Vivo Ameliorates Maternal Diabetes Mellitus–Induced Apoptosis and Heart Defects Through Restoration of Impaired Wnt Signaling

Abstract

Background Oxidative stress is manifested in embryos exposed to maternal diabetes, yet specific mechanisms for diabetes-induced heart defects are not defined. Gene deletion of intermediates of Wingless-related integration (Wnt) signaling causes heart defects similar to those observed in embryos from diabetic pregnancies. We tested the hypothesis that diabetes-induced oxidative stress impairs Wnt signaling thereby causing heart defects, and that these defects can be rescued by transgenic overexpression of the reactive oxygen species scavenger SOD1. Methods and Results Wild-type (WT) and superoxide dismutase 1 (SOD1) overexpressing embryos from nondiabetic WT control dams and nondiabetic/diabetic WT female mice mated with SOD1 transgenic male mice were analyzed. No heart defects were observed in WT and SOD1 embryos under nondiabetic conditions. WT embryos of diabetic dams had a 26% incidence of cardiac outlet defects that were suppressed by SOD1 overexpression. Insulin treatment reduced blood glucose levels and heart defects. Diabetes increased superoxide production, canonical Wnt antagonist expression, caspase activation, and apoptosis, and suppressed cell proliferation. Diabetes suppressed Wnt signaling intermediates and Wnt target gene expression in the embryonic heart, each of which were reversed by SOD1 overexpression. Hydrogen peroxide and peroxynitrite mimicked the inhibitory effect of high glucose on Wnt signaling, which was abolished by the SOD1 mimetic, tempol. Conclusions The oxidative stress of diabetes impairs Wnt signaling and causes cardiac outlet defects that are rescued by SOD1 overexpression. This suggests that targeting of components of the Wnt5a signaling pathway may be a viable strategy for suppression of CHDs in fetuses of diabetic pregnancies.

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

“…Reduced cardiomyocyte proliferation and Cyclin D1 transcript expression was noticed in E13.5 embryos exposed to matDM (Supplemental Figure 9, A-J), which is either due to excess ROS production or the secondary effect of Notch1 downregulation in endocardial/endocardial-derived cells; however, the mechanism leading to VSD is beyond the scope of this study. It has been shown that overexpression of the superoxide dismutase (SOD) gene rescues CHD phenotypes in the offspring of mice with matDM but this may overexpression system may have numerous effects apart from decreased ROS (68). Similarly, NAC treatment of severely diabetic mice (average blood glucose >450 mg/dl) has been shown to partially rescue the CHD phenotypes (69).…”

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

“…Our recent studies demonstrated in the T1DM that impaired Wnt signaling and activation of the proapoptotic kinase apoptosis signal-regulating kinase 1 are involved in the induction of heart defects. 24,39 Future studies will reveal whether alterations of these signaling pathways contribute to the etiology of T2DM-induced heart defects.…”

The green tea polyphenol EGCG alleviates maternal diabetes–induced neural tube defects by inhibiting DNA hypermethylation

“…1,8,56 Although the efficacy of general antioxidants, including folic acid, in reducing adverse pregnancy outcomes is controversial, 74–76 antioxidants with specific inhibitory effects on DNA methylation, such as Epigallocatechin gallate, may be better therapeutics.…”