Cell protective mechanism of valproic acid in lethal hemorrhagic shock.
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 beta-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 beta-catenin, and Bcl-2 by Western blot. In addition, primary neurons dissociated from E18 rat embryos were exposed to hypoxia (0.5% O(2)) for 16 hours with or without VPA (1 mmol/L) and analyzed using confocal microscopy.


RESULTS
After treatment of hemorrhaged animals with VPA, acetylated beta-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, beta-catenin translocated into the nucleus and colocalized with Ac-H3K9.


CONCLUSIONS
VPA treatment acetylates H3K9 and beta-catenin and enhances translocation of beta-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 beta-catenin survival pathway.
Li
Yongqing
Y
Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA.
Liu
Baoling
B
Sailhamer
Elizabeth A
EA
Yuan
Zengqiang
Z
Shults
Christian
C
Velmahos
George C
GC
deMoya
Marc
M
Shuja
Fahad
F
Butt
Muhammad U
MU
Alam
Hasan B
HB
D000107:Acetylation; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D003600:Cytosol; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2 / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D012771:Shock, Hemorrhagic / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D019253:Proto-Oncogene Proteins c-bcl-2; D051176:beta Catenin; D014635:Valproic Acid