title: Hypoxic switch in mitochondrial myeloid cell leukemia factor-1/Mtd apoptotic rheostat contributes to human trophoblast cell death in preeclampsia.
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.
authors.affiliation: Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Nima
authors.initials: N
authors.lastname: Soleymanlou
authors.forename: Andrea
authors.initials: A
authors.lastname: Jurisicova
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Mari
authors.initials: M
authors.lastname: Chijiiwa
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Ray
authors.forename: Jacqui
authors.initials: J
authors.lastname: Detmar
authors.forename: Tullia
authors.initials: T
authors.lastname: Todros
authors.forename: Stacy
authors.initials: S
authors.lastname: Zamudio
authors.forename: Martin
authors.initials: M
authors.lastname: Post
authors.forename: Isabella
authors.initials: I
authors.lastname: Caniggia
mesh_terms: D000293:Adolescent; D000328:Adult; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007150:Immunohistochemistry; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010100:Oxygen / Q000494:pharmacology; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011225:Pre-Eclampsia / Q000235:genetics / Q000503:physiopathology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015686:Gene Products, env; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C405335:syncytin; D020169:Caspases; D010100:Oxygen