Caspase-8: a key role in the pathogenesis of diabetic embryopathy.
Maternal diabetes causes neural tube defects in embryos, which are associated with increased apoptosis in the neuroepithelium. Many factors, including effector caspases, have been shown to be involved in the events. However, the key regulators have not been identified and the underlying mechanisms remain to be addressed. Caspase-8, an initiator caspase, has been shown to be altered in diabetic embryopathy, suggesting a role as an upstream apoptotic regulator. Using mouse embryos as a model system, this study demonstrates that caspase-8 is required for the production of hyperglycemia-associated embryonic malformations. Caspase-8 was shown to be expressed in the developing neural tube. Its activity, as evidenced by enhanced cleavage, was increased by hyperglycemia. These changes were associated with increased formation of the active cleavage of Bid. Inhibition of caspase-8 activity in high glucose-challenged embryos reduced the rate of embryonic malformation and this was associated with decreased apoptosis in the neuroepithelium of the neural tube. Inhibition of caspase-8 activity also reduced hyperglycemia-induced Bid activation and caspase-9 cleavage. These data suggest that caspase-8 may control diabetic embryopathy-associated apoptosis via regulation of the Bid-stimulated mitochondrion/caspase-9 pathway.
Zhao
Zhiyong
Z
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA. zzhao@upi.umaryland.edu
Yang
Peixin
P
Eckert
Richard L
RL
Reece
E Albert
EA
D000014:Abnormalities, Drug-Induced / Q000201:enzymology* / Q000209:etiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005947:Glucose / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D051379:Mice; D054259:Neural Tube / Q000002:abnormalities / Q000201:enzymology*; D009436:Neural Tube Defects / Q000201:enzymology* / Q000209:etiology; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000201:enzymology* / Q000209:etiology
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D005947:Glucose