Hepatoprotection and lethality rescue by histone deacetylase inhibitor valproic acid in fatal hemorrhagic shock.
BACKGROUND
Pharmacological histone deacetylase (HDAC) inhibitors, such as known anticonvulsant valproic acid (VPA), demonstrate cytoprotective effects and increase acetylation of nuclear histones, promoting transcriptional activation of deregulated genes. Therefore, we examined protective effects of VPA administration in lethal hemorrhage and analyzed the patterns of hepatic histone acetylation.


METHODS
Male Wistar Kyoto rats were pretreated with VPA (n = 10) and 2-methyl-2-pentenoic acid (2M2P), structural VPA analog with limited HDAC inhibiting activity (2M2P; n = 8), at 300 mg/kg/dose, administered subcutaneously, 24 hour and immediately before lethal, if untreated, hemorrhage was induced by removing the 60% of total blood volume. Both drugs were dissolved in normal saline (NS) and rats pretreated with corresponding volume of NS served as control group (n = 8). Time to death, the degree of histone acetylation in liver, HDAC activity and markers of cytotoxicity (alpha-glutathione S-transferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and lactate), and apoptosis were analyzed.


RESULTS
VPA-pretreated animals demonstrated five-fold increase in survival duration. At 12 hours posthemorrhage, 70% (VPA) and 12% (2M2P) pretreated rats were alive versus 0% in NS group. Hyperacetylation of histones H2A, H3, and H4 indicated the presence of active genes and correlated with survival (VPA > 2M2P > NS). Hemorrhage-induced increases in lactate, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were alleviated by VPA. Moreover, alpha-glutathione S-transferase release, indicative of liver damage, was completely abolished.


CONCLUSIONS
VPA offers considerable protection in severe hemorrhagic shock. The role of HDAC inhibition is suggested in mediating prosurvival actions of VPA.
Gonzales
Earl R
ER
Department of Surgery, Trauma Research and Readiness Institute for Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
Chen
Huazhen
H
Munuve
Richard M
RM
Mehrani
Tina
T
Nadel
Amal
A
Koustova
Elena
E
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D012771:Shock, Hemorrhagic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid