1. ¹Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5
2. ²The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8
3. ³Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
4. ⁴Department of Obstetrics and Gynecology, Maternal-Fetal Medicine Unit, University of Turin, Italy
5. ⁵Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
6. ⁶Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Correspondence: I Caniggia, Mount Sinai Hospital, Samuel Lunenfeld Research Institute, 600 University Avenue, Room 871C, Toronto, Ontario, Canada M5G 1X5. Tel: +1 416 586 4803; Fax: +1 416 586 8588; E-mail: caniggia@mshri.on.ca

Received 29 July 2004; Revised 29 November 2004; Accepted 28 December 2004; Published online 18 March 2005.

Abstract

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.