Decoding the oxidative stress hypothesis in diabetic embryopathy through proapoptotic kinase signaling

Abstract

Maternal diabetes-induced birth defects occur in 6-10% of babies born to mothers with pregestational diabetes, representing a significant maternal-fetal health problem. Currently, these congenital malformations represent a significant maternal-fetal medicine issue, but are likely to create an even greater public health threat as 3 million women of reproductive age (19-44 years) have diabetes in the United States alone, and this number is expected to double by 2030. Neural tube defects (NTDs) and congenital heart defects are the most common types of birth defects associated with maternal diabetes. Animal studies have revealed that embryos under hyperglycemic conditions exhibit high levels of oxidative stress resulting from enhanced production of reactive oxygen species and impaired antioxidant capability. Oxidative stress activates a set of pro-apoptotic kinase signaling intermediates leading to abnormal cell death in the embryonic neural tube, which causes NTD formation. Work in animal models also has revealed that maternal diabetes triggers a series of signaling intermediates: protein kinase C (PKC) isoforms, PKCα, βII and δ; apoptosis signal-regulating kinase 1 (ASK1), c-Jun-N-terminal kinase 1/2 (JNK1/2), caspase and apoptosis. Specifically, maternal diabetes in rodent models activates the pro-apoptotic unfolded protein response and endoplasmic reticulum (ER) stress. A reciprocal causation between JNK1/2 activation and ER stress exists in diabetic embryopathy. Molecular studies further demonstrate that deletion of the genes for PKCα, Ask1, Jnk1 or Jnk2 abolishes maternal diabetes-induced neural progenitor apoptosis and ameliorates NTD formation. Similar preventive effects are also observed when ASK1, JNK1/2 or ER stress is inhibited. Cell membrane stabilizers and antioxidant supplements are also effective in prevention of diabetes-induced birth defects. Mechanistic studies have revealed important insights into our understanding the cause of diabetic embryopathy and have provided a basis for future interventions against birth defects or other pregnancy complications associated with maternal diabetes. The knowledge of a molecular pathway map identified in animal studies has created unique opportunities to identify molecular targets for therapeutic intervention.

Punicalagin exerts protective effect against high glucose-induced cellular stress and neural tube defects

“…Both oxidative stress and ER stress converge on the induction of aberrant apoptosis, a hallmark of diabetic embryopathy[10, 11, 30, 34]. Previous work by Chen et al demonstrated that punicalagin can protect human trophoblasts from stress-induced apoptosis 22 .…”

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development

“…Maternal diabetes induces oxidative stress in the developing embryo (6,9,26,45,48,53,58,59) and activates apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase (MAPK) kinase, in neurulation stage embryos (47,57). ASK1 responds to oxidative stress and induces apoptosis via the activation of c-Jun NH 2 -terminal kinase 1/2 (JNK) and/or p38 MAPK (42).…”

New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects

“…Apoptosis has been hypothesized as a primary mechanism of diabetes-induced birth defects 57–59 . Under euglycemic conditions, very low basal levels of apoptosis are observed in the embryonic tissues during organogenesis (E7-E11) 60 .…”

“…However, the apoptotic mechanism in this disease process is not well understood. Evidence from clinical and experimental studies has revealed that maternal diabetes leads to an imbalance in intracellular reduction-oxidation (redox) homeostasis, resulting in intracellular oxidative stress 57–59,67–70 . Recent studies have demonstrated that oxidative stress and ER stress are the main biochemical and molecular mechanisms underlying maternal diabetes- induced apoptosis 66,71–75 .…”

“…ASK1 activation leads to apoptosis via the JNK or the p38MAP kinase pathways 80 . ASK1 is activated by phosphorylation of Thr-845 in its activation loop, and ASK1 is required for reactive oxygen species (ROS)- and endoplasmic reticulum (ER) stress-induced JNK activation and apoptosis 58,59,80,84–86 . Recently, it has been shown that high glucose-induced activation of ASK1 mediates hyperglycemia-induced endothelial cell senescence 87 .…”