Protein kinase Cβ2 inhibition reduces hyperglycemia-induced neural tube defects through suppression of a caspase 8-triggered apoptotic pathway

OBJECTIVE: Neural tube defects in diabetic embryopathy are associated with increased protein kinase C (PKC)beta 2 activity and programmed cell death (apoptosis). The apoptosis is triggered by caspase 8, which activates members of the Bcl-2 and caspase families, such as Bid and caspase 3. Whether PKC beta 2 regulates caspase 8-induced apoptosis remains to be addressed. STUDY DESIGN: Mouse embryos at embryonic day 8.5 were cultured in a high concentration of glucose (22 mmol/L) and treated with PKC beta 2 inhibitor (50 nmol/L) for 48 hours. The levels of apoptosis and activation of apoptotic factors were quantified using the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and Western blot assays, respectively. RESULTS: Reduction in the rate of neural tube defect by PKC beta 2 inhibition is associated with significant decreases in the levels of apoptosis, and caspase 8, caspase 3, and Bid activation, and cytochrome C release from mitochondria, to the similar levels as in euglycemic controls (8.3 mmol/L; P < .05). CONCLUSION: PKC beta 2 influences a caspase 8-regulated apoptotic pathway in diabetic embryopathy.