Decreased glucose transporter expression triggers BAX-dependent apoptosis in the murine blastocyst.
We report that a decrease in facilitative glucose transporter (GLUT1) expression and reduced glucose transport trigger apoptosis in the murine blastocyst. Inhibition of GLUT1 expression either by high glucose conditions or with antisense oligodeoxynucleotides significantly lowers protein expression and function of GLUT1 and as a result induces a high rate of apoptosis at the blastocyst stage. Similar to wild-type mice, embryos from streptozotocin-induced diabetic Bax -/- mice experienced a significant decrease in glucose transport compared with embryos from non-diabetic Bax -/- mice. However, despite this decrease, these blastocysts demonstrate significantly fewer apoptotic nuclei as compared with blastocysts from hyperglycemic wild-type mice. This decrease in preimplantation apoptosis correlates with a decrease in resorptions and malformations among the infants of the hyperglycemic Bax -/- mice versus the Bax +/+ and +/- mice. These findings suggest that hyperglycemia by decreasing glucose transport acts as a cell death signal to trigger a BAX-dependent apoptotic cascade in the murine blastocyst. This work also supports the hypothesis that increased apoptosis at a blastocyst stage because of maternal hyperglycemia may result in loss of key progenitor cells and manifest as a resorption or malformation, two adverse pregnancy outcomes more common in diabetic women.
Chi
M M
MM
Departments of Obstetrics/Gynecology and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Pingsterhaus
J
J
Carayannopoulos
M
M
Moley
K H
KH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control; D005260:Female; D005315:Fetal Diseases / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D051272:Glucose Transporter Type 1; D051379:Mice; D015335:Molecular Probes; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D051272:Glucose Transporter Type 1; D015335:Molecular Probes; D009004:Monosaccharide Transport Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C495678:Slc2a1 protein, mouse; D051028:bcl-2-Associated X Protein