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

Dong Y, Ito T, Velayo C, Sato T, Iida K, Endo M, Funamoto K, Sato N, Yaegashi N, Kimura Y - PLoS ONE (2014)

Bottom Line: In the present work, pregnant mice were exposed to IR on day 18 of gestation by clipping one side of the maternal uterine horn.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.

View Article: PubMed Central - PubMed

Affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.

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.

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Related in: MedlinePlus

P53 mRNA was increased response to IR in the fetal brain.Within 30 minutes post-IR, the mRNA levels of Mapk associated proteins, except Jnk2 and Trp53 (p53), were noted to have increased, while Hif-1α, Mdm2 and Ccm3/Pdcd10 were not increased as compared to the housekeeping gene Hprt1. (n = 12 from at least 3 individual pregnant mice). p<0.05 indicated as single star and p<0.01 indicated as two stars.
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pone-0110577-g004: P53 mRNA was increased response to IR in the fetal brain.Within 30 minutes post-IR, the mRNA levels of Mapk associated proteins, except Jnk2 and Trp53 (p53), were noted to have increased, while Hif-1α, Mdm2 and Ccm3/Pdcd10 were not increased as compared to the housekeeping gene Hprt1. (n = 12 from at least 3 individual pregnant mice). p<0.05 indicated as single star and p<0.01 indicated as two stars.

Mentions: To investigate new protein synthesis after IR, full gene expression in fetal brain was evaluated by microarray analysis (Figure 4). Within 30 minutes after IR, the expressions of Mapk genes were increased except for Jnk2. Within 30 minutes after IR, the mRNA level of p53 was noted to have been increased, while Hif-1α was not increased as compared to the housekeeping gene Hprt1.


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

Dong Y, Ito T, Velayo C, Sato T, Iida K, Endo M, Funamoto K, Sato N, Yaegashi N, Kimura Y - PLoS ONE (2014)

P53 mRNA was increased response to IR in the fetal brain.Within 30 minutes post-IR, the mRNA levels of Mapk associated proteins, except Jnk2 and Trp53 (p53), were noted to have increased, while Hif-1α, Mdm2 and Ccm3/Pdcd10 were not increased as compared to the housekeeping gene Hprt1. (n = 12 from at least 3 individual pregnant mice). p<0.05 indicated as single star and p<0.01 indicated as two stars.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4201554&req=5

pone-0110577-g004: P53 mRNA was increased response to IR in the fetal brain.Within 30 minutes post-IR, the mRNA levels of Mapk associated proteins, except Jnk2 and Trp53 (p53), were noted to have increased, while Hif-1α, Mdm2 and Ccm3/Pdcd10 were not increased as compared to the housekeeping gene Hprt1. (n = 12 from at least 3 individual pregnant mice). p<0.05 indicated as single star and p<0.01 indicated as two stars.
Mentions: To investigate new protein synthesis after IR, full gene expression in fetal brain was evaluated by microarray analysis (Figure 4). Within 30 minutes after IR, the expressions of Mapk genes were increased except for Jnk2. Within 30 minutes after IR, the mRNA level of p53 was noted to have been increased, while Hif-1α was not increased as compared to the housekeeping gene Hprt1.

Bottom Line: In the present work, pregnant mice were exposed to IR on day 18 of gestation by clipping one side of the maternal uterine horn.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.

View Article: PubMed Central - PubMed

Affiliation: Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.

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.

Show MeSH
Related in: MedlinePlus