Intrauterine ischemic reperfusion switches the fetal transcriptional pattern from HIF-1α- to P53-dependent regulation in the murine brain

• Published in: PloS one Vol. 9; no. 10; p. e110577
• Main Authors: Dong, Yupeng, Ito, Takuya, Velayo, Clarissa, Sato, Takafumi, Iida, Keita, Endo, Miyuki, Funamoto, Kiyoe, Sato, Naoaki, Yaegashi, Nobuo, Kimura, Yoshitaka
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.10.2014; Public Library of Science (PLoS)
• Subjects: AKT protein; Animals; Apoptosis; Benzothiazoles - administration & dosage; Biology and Life Sciences; Biomedical engineering; Brain; Brain damage; Brain Injuries - metabolism; Brain Injuries - pathology; Brain injury; Cell cycle; Cytokines; Damage prevention; Edema; EKG; Electrocardiography; Engineering; Female; Fetus - pathology; Fetuses; Fractals; Gene expression; Gene Expression Regulation - drug effects; Gene regulation; Gestation; Gynecology; Heart rate; Hemorrhage; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Interdisciplinary aspects; Ischemia; Kinases; Medical prognosis; Medical research; Medicine; Medicine and Health Sciences; Mice; Molecular modelling; Obstetrics; p53 Protein; Phosphorylation; Pregnancy; Protein biosynthesis; Protein synthesis; Proteins; Reperfusion; Research and Analysis Methods; Rodents; Signal Transduction - drug effects; Switches; Toluene - administration & dosage; Toluene - analogs & derivatives; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Transcription; Traumatic brain injury; Tumor Suppressor Protein p53 - metabolism; University graduates; Uterus; Uterus - metabolism; Uterus - pathology; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0110577

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.