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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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In vivo, PFT-α inhibition of protein synthesis after IR.(A) PFT-α inhibited phosphorylation of S6 in fetal brain. (B) Measurement phosphorylated S6 (Vs. beta actin, n = 4∼6 from at least 3 individual pregnant mice). White means fetal brain and black means fetal heart.
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pone-0110577-g007: In vivo, PFT-α inhibition of protein synthesis after IR.(A) PFT-α inhibited phosphorylation of S6 in fetal brain. (B) Measurement phosphorylated S6 (Vs. beta actin, n = 4∼6 from at least 3 individual pregnant mice). White means fetal brain and black means fetal heart.

Mentions: To confirm whether P53 dependent cell death such as apoptosis was activated after IR, we studied the phosphorylation of S6. IR suppressed the phosphorylation of S6 and this was further suppressed by a p53 inhibitor, PFT-α (Figure 7). The action of PFT-α, a mitochondrial p53 inhibitor, in inhibiting P53 protein and transcriptional activity was consistent with previous reports [23], [24]. Overall, our findings suggested that P53 dependent protein synthesis was activated by IR.


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)

In vivo, PFT-α inhibition of protein synthesis after IR.(A) PFT-α inhibited phosphorylation of S6 in fetal brain. (B) Measurement phosphorylated S6 (Vs. beta actin, n = 4∼6 from at least 3 individual pregnant mice). White means fetal brain and black means fetal heart.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110577-g007: In vivo, PFT-α inhibition of protein synthesis after IR.(A) PFT-α inhibited phosphorylation of S6 in fetal brain. (B) Measurement phosphorylated S6 (Vs. beta actin, n = 4∼6 from at least 3 individual pregnant mice). White means fetal brain and black means fetal heart.
Mentions: To confirm whether P53 dependent cell death such as apoptosis was activated after IR, we studied the phosphorylation of S6. IR suppressed the phosphorylation of S6 and this was further suppressed by a p53 inhibitor, PFT-α (Figure 7). The action of PFT-α, a mitochondrial p53 inhibitor, in inhibiting P53 protein and transcriptional activity was consistent with previous reports [23], [24]. Overall, our findings suggested that P53 dependent protein synthesis was activated by IR.

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