Published online before print June 28, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070094

Accepted for publication April 13, 2007.

Article

Hypoxic Switch in Mitochondrial Myeloid Cell Leukemia Factor-1/Mtd Apoptotic Rheostat Contributes to Human Trophoblast Cell Death in Preeclampsia

Nima Soleymanlou^*, Andrea Jurisicova^*, Yuanhong Wu^*, Mari Chijiiwa^*, Jocelyn E. Ray^*, Jacqui Detmar^*, Tullia Todros^¶, Stacy Zamudio^||, Martin Post^**, and Isabella Caniggia^*@

From Mount Sinai Hospital,* Toronto, Ontario, Canada; The Hospital for Sick Children, Toronto, Ontario, Canada; the Departments of Physiology, Obstetrics and Gynecology, and Pediatrics,** Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; the Department of Obstetrics and Gynecology,^¶ Unit of Maternal-Fetal Medicine, University of Turin, Turin, Italy; and New Jersey Medical School,^|| Newark, New Jersey

^@ To whom correspondence should be addressed. E-mail: caniggia{at}mshri.on.ca.

	Abstract

Preeclampsia, a disorder of pregnancy, is characterized by increased trophoblast cell death and altered trophoblast-mediated remodeling of myometrial spiral arteries resulting in reduced uteroplacental perfusion. Mitochondria-associated Bcl-2 family members are important regulators of programed cell death. The mechanism whereby hypoxia alters the mitochondrial apoptotic rheostat is essential to our understanding of placental disease. Herein, myeloid cell leukemia factor-1 (Mcl-1) isoform expression was examined in physiological/pathological models of placental hypoxia. Preeclamptic placentae were characterized by caspase-dependent cleavage of death-suppressing Mcl-1L and switch toward cell death-inducing Mcl-1S. In vitro, Mcl-1L cleavage was induced by hypoxia-reoxygenation in villous explants, whereas Mcl-1L overexpression under hypoxia-reoxygenation rescued trophoblast cells from undergoing apoptosis. Cleavage was mediated by caspase-3/-7 because pharmacological caspase inhibition prevented this process. Altitude-induced chronic hypoxia was characterized by expression of Mcl-1L; resulting in a reduction of apoptotic markers (cleaved caspase-3/-8 and p85 poly-ADP-ribose polymerase). Moreover, in both physiological (explants and high altitude) and pathological (preeclampsia) placental hypoxia, decreased trophoblast syncytin expression was observed. Hence, although both pathological and physiological placental hypoxia are associated with slowed trophoblast differentiation, trophoblast apoptosis is only up-regulated in preeclampsia, because of a hypoxia-reoxygenation-induced switch in generation of proapoptotic Mcl-1 isoforms.