title: Intrauterine ischemic reperfusion switches the fetal transcriptional pattern from HIF-1α- to P53-dependent regulation in the murine brain.
abstract: Ischemic reperfusion (IR) during the perinatal period is a known causative factor of fetal brain damage. So far, both morphologic and histologic evidence has shown that fetal brain damage can be observed only several hours to days after an IR insult has occurred. Therefore, to prevent fetal brain damage under these circumstances, a more detailed understanding of the underlying molecular mechanisms involved during an acute response to IR is necessary. In the present work, pregnant mice were exposed to IR on day 18 of gestation by clipping one side of the maternal uterine horn. Simultaneous fetal electrocardiography was performed during the procedure to verify that conditions resulting in fetal brain damage were met. Fetal brain sampling within 30 minutes after IR insult revealed molecular evidence that a fetal response was indeed triggered in the form of inhibition of the Akt-mTOR-S6 synthesis pathway. Interestingly, significant changes in mRNA levels for both HIF-1α and p53 were apparent and gene regulation patterns were observed to switch from a HIF-1α-dependent to a p53-dependent process. Moreover, pre-treatment with pifithrin-α, a p53 inhibitor, inhibited protein synthesis almost completely, revealing the possibility of preventing fetal brain damage by prophylactic pifithrin-α treatment.
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ito
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Velayo
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Iida
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Endo
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kiyoe
authors.initials: K
authors.lastname: Funamoto
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Obstetrics & Gynecology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
authors.affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Obstetrics & Gynecology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kimura
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005333:Fetus / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D011247:Pregnancy; D015424:Reperfusion; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014050:Toluene / Q000008:administration & dosage / Q000031:analogs & derivatives; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014599:Uterus / Q000378:metabolism* / Q000473:pathology
chemical_list: D052160:Benzothiazoles; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases