Hyperglycemia induces apoptosis in pre-implantation embryos through cell death effector pathways

作者: K.H. Moley , M.M.-Y. Chi , C.M. Knudson , S.J. Korsmeyer , M.M. Mueckler

DOI: 10.1038/4013

关键词: InsulinCaspaseInternal medicineApoptosisBcl-2-associated X proteinEndocrinologyBlastocystDNA fragmentationBiologyIn vivoProgrammed cell deathGeneral Biochemistry, Genetics and Molecular BiologyGeneral Medicine

摘要: Although perinatal mortality rates have improved for pregnant diabetic women because of insulin therapy and tight metabolic control, infants diabetics still experience significantly higher congenital malformations spontaneous miscarriages compared with those non-diabetic women. Our results here indicate that hyperglycemic conditions, either in vivo or vitro, modulate the expression an apoptosis regulatory gene as early pre-implantation blastocyst stage mouse. Apoptosis mammalian is a normal process, thought to protect embryo by eliminating abnormal cells. Here we demonstrate Bax, Bcl-2-like protein, increased at presence high concentrations glucose, these changes correlate morphologically DNA fragmentation. Expression Bax caspase are necessary this vitro glucose-induced apoptotic event, ceramide involved mediating embryotoxic effect glucose. We also show cellular can be prevented treating mice before immediately after conception. These findings emphasize importance glycemic control earliest stages

参考文章(23)
Fuad N. Ziyadeh, Eric G. Neilson, Alberto Ortiz, Expression of apoptosis-regulatory genes in renal proximal tubular epithelial cells exposed to high ambient glucose and in diabetic kidneys. Journal of Investigative Medicine. ,vol. 45, pp. 50- 56 ,(1997)
E. Wang, W.P. Norred, C.W. Bacon, R.T. Riley, A.H. Merrill, Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme. Journal of Biological Chemistry. ,vol. 266, pp. 14486- 14490 ,(1991) , 10.1016/S0021-9258(18)98712-0
Arul M. Chinnaiyan, Kim Orth, Karen O'Rourke, Hangjun Duan, Guy G. Poirier, Vishva M. Dixit, Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases. Journal of Biological Chemistry. ,vol. 271, pp. 4573- 4576 ,(1996) , 10.1074/JBC.271.9.4573
Janine E. Polifka, Joe C. Rutledge, Gary L. Kimmel, Vicki Dellarco, Walderico M. Generoso, Exposure to ethylene oxide during the early zygotic period induces skeletal anomalies in mouse fetuses Teratology. ,vol. 53, pp. 1- 9 ,(1996) , 10.1002/(SICI)1096-9926(199601)53:1<1::AID-TERA1>3.0.CO;2-A
Gloria I. Perez, C. Michael Knudson, Lucy Leykin, Stanley J. Korsmeyer, Jonathan L. Tilly, APOPTOSIS-ASSOCIATED SIGNALING PATHWAYS ARE REQUIRED FOR CHEMOTHERAPY-MEDIATED FEMALE GERM CELL DESTRUCTION Nature Medicine. ,vol. 3, pp. 1228- 1232 ,(1997) , 10.1038/NM1197-1228
C. M. Knudson, K. S. K. Tung, W. G. Tourtellotte, G. A. J. Brown, S. J. Korsmeyer, Bax-deficient mice with lymphoid hyperplasia and male germ cell death Science. ,vol. 270, pp. 96- 99 ,(1995) , 10.1126/SCIENCE.270.5233.96
M D Jacobsen, M Weil, M C Raff, Role of Ced-3/ICE-family proteases in staurosporine-induced programmed cell death. Journal of Cell Biology. ,vol. 133, pp. 1041- 1051 ,(1996) , 10.1083/JCB.133.5.1041
Ron Bose, Marcel Verheij, Adriana Haimovitz-Friedman, Kathleen Scotto, Zvi Fuks, Richard Kolesnick, Ceramide synthase mediates daunorubicin-induced apoptosis: An alternative mechanism for generating death signals Cell. ,vol. 82, pp. 405- 414 ,(1995) , 10.1016/0092-8674(95)90429-8
Patrick P. L. Tam, Postimplantation development of mitomycin C-treated mouse blastocysts Teratology. ,vol. 37, pp. 205- 212 ,(1988) , 10.1002/TERA.1420370305
K. H. Moley, W. K. Vaughn, A. H. DeCherney, M. P. Diamond, Effect of diabetes mellitus on mouse pre-implantation embryo development Reproduction. ,vol. 93, pp. 325- 332 ,(1991) , 10.1530/JRF.0.0930325