A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia.
Pre-eclampsia is a serious disorder of human pregnancy, characterized by decreased utero-placental perfusion and increased trophoblast cell death. Presently, the mechanisms regulating trophoblast cell death in pre-eclampsia are not fully elucidated. Herein, we have identified a novel Mtd/Bok splice isoform (Mtd-P) resulting from exon-II skipping. Mtd-P expression was unique to early-onset severe pre-eclamptic placentae as assessed by quantitative real-time-PCR and immunoblotting. Mtd-P overexpression in cell lines (BeWo: cytotrophoblast-derived; and CHO: ovary-derived) resulted in increased apoptotic cell death as assessed by caspase-3 cleavage, internucleosomal DNA laddering and mitochondrial depolarization. Moreover, Mtd-P expression increased under conditions of low oxygenation/oxidative stress in human villous explants. Antisense knockdown of Mtd under conditions of oxidative stress resulted in decreased caspase-3 cleavage. We conclude that under conditions of reduced oxygenation/oxidative stress, Mtd-P causes trophoblast cell death in pre-eclampsia and hence may contribute to the molecular events leading to the clinical manifestations of this disease.
Soleymanlou
N
N
Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
Wu
Y
Y
Wang
J X
JX
Todros
T
T
Ietta
F
F
Jurisicova
A
A
Post
M
M
Caniggia
I
I
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D016923:Cell Death; D005260:Female; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D010920:Placenta / Q000166:cytology; D011225:Pre-Eclampsia / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014327:Trophoblasts / Q000473:pathology*
C503049:BOK protein, human; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2