Cell protective mechanism of valproic acid in lethal hemorrhagic shock

Yongqing Li, Baoling Liu, Elizabeth A. Sailhamer, Zengqiang Yuan, Christian Shults, George C. Velmahos, Marc deMoya, Fahad Shuja, Muhammad U. Butt, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Background: We have demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve animal survival after hemorrhagic shock and protect neurons from hypoxia-induced apoptosis. This study investigated whether VPA treatment works through the β-catenin survival pathways. Methods: Wistar-Kyoto rats underwent hemorrhagic shock (60% blood loss) followed by treatment with or without VPA (300 mg/kg). Brains were harvested after 1, 6, and 24 hours and analyzed for acetylated histone-H3 at lysine-9 (Ac-H3K9), acetylated and total β-catenin, and Bcl-2 by Western blot. In addition, primary neurons dissociated from E18 rat embryos were exposed to hypoxia (0.5% O2) for 16 hours with or without VPA (1 mmol/L) and analyzed using confocal microscopy. Results: After treatment of hemorrhaged animals with VPA, acetylated β-catenin was found in both the cytosol and nucleus, along with Ac-H3K9. Bcl-2 transcript increased after 1 hour followed by an increase in Bcl-2 protein at 6 hours. Confocal imaging demonstrated that after VPA treatment, β-catenin translocated into the nucleus and colocalized with Ac-H3K9. Conclusion: VPA treatment acetylates H3K9 and β-catenin and enhances translocation of β-catenin into the nucleus, where it colocalizes with Ac-H3K9 and stimulates the transcription of survival gene bcl-2. This finding suggests that VPA protects cells after severe insult through the β-catenin survival pathway.

Original languageEnglish (US)
Pages (from-to)217-224
Number of pages8
JournalSurgery
Volume144
Issue number2
DOIs
StatePublished - Aug 2008
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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