Valproic acid protects against haemorrhagic shock-induced signalling changes via PPARγ activation in an in vitro model

British Journal of Pharmacology
Alexandra M E ZuckermannRobin S B Williams

Abstract

Valproic acid (VPA), a widely used epilepsy and bipolar disorder treatment, provides acute protection against haemorrhagic shock-induced mortality in a range of in vivo models through an unknown mechanism. In the liver, this effect occurs with a concomitant protection against a decrease in GSK3β-Ser(9) phosphorylation. Here, we developed an in vitro model to investigate this protective effect of VPA and define a molecular mechanism. The human hepatocarcinoma cell line (Huh7) was exposed to conditions occurring during haemorrhagic shock (hypoxia, hypercapnia and hypothermia) to investigate the changes in GSK3β-Ser(9) phosphorylation for a 4 h period following treatment with VPA, related congeners, PPAR agonists, antagonists and siRNA. Huh7 cells undergoing combined hypoxia, hypercapnia, and hypothermia reproduced the reduced GSK3β-Ser(9) phosphorylation shown in vivo during haemorrhagic shock, and this change was blocked by VPA. The protective effect occurred through upstream PTEN and Akt signalling, and prevented downstream β-catenin degradation while increasing histone 2/3 acetylation. This effect was reproduced by several VPA-related compounds with known PPARγ agonist activity, independent of histone deacetylase (HDAC) inhibi...Continue Reading

References

Feb 1, 1991·Clinical Pharmacokinetics·M Bialer
Aug 18, 1995·Journal of Medicinal Chemistry·J Palaty, F S Abbott
Sep 2, 1997·Proceedings of the National Academy of Sciences of the United States of America·H Eldar-Finkelman, E G Krebs
Sep 16, 1998·Proceedings of the National Academy of Sciences of the United States of America·M DelcommenneS Dedhar
May 26, 1999·Proceedings of the National Academy of Sciences of the United States of America·H SunH Wu
Mar 15, 2002·Current Opinion in Genetics & Development·Shelley L Berger
May 17, 2002·Nature·Robin S B WilliamsAdrian J Harwood
Jul 3, 2002·Molecular and Cellular Neurosciences·Anita C HallPatricia C Salinas
Jul 5, 2002·The Journal of Biological Chemistry·Jenny CarmichaelDavid C Rubinsztein
Nov 6, 2002·Journal of Biochemistry·Chie Sakanaka
Nov 8, 2002·Emergency Medicine Journal : EMJ·F E LeckyUNKNOWN Trauma Audit and Research Network
May 14, 2003·Journal of the American College of Surgeons·Mary E KellerErwin F Hirsch
Aug 21, 2003·Biochemical and Biophysical Research Communications·Anthony F TramontanoNabil El-Sherif
Sep 5, 2003·Emergency Medicine Journal : EMJ·L A Wallis, H Guly
Dec 23, 2003·Laboratory Investigation; a Journal of Technical Methods and Pathology·Gina HotterAnna Sola
Feb 12, 2004·Cancer Research·Nadia GurvichPeter S Klein
Mar 17, 2004·Biochimica Et Biophysica Acta·Masahito HanadaBrian A Hemmings
Oct 8, 2004·Critical Care : the Official Journal of the Critical Care Forum·Guillermo GutierrezMarian E Wulf-Gutierrez
Jan 5, 2005·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Bhavani Prasad KotaBasil D Roufogalis
May 19, 2005·Bipolar Disorders·W Jonathan RyvesRobin Sb Williams
Oct 14, 2005·Critical Care : the Official Journal of the Critical Care Forum·David S Kauvar, Charles E Wade
Jan 27, 2006·The New England Journal of Medicine·Ellen J MacKenzieDaniel O Scharfstein
Sep 1, 2006·Neurochemical Research·Richard S JopeEléonore Beurel
Sep 19, 2006·Shock·Rolf RossaintDonat R Spahn
Jan 3, 2007·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Meir Bialer, Boris Yagen
Dec 20, 2007·Journal of Neurochemistry·Claudie HooperSimon Lovestone
Dec 28, 2007·Seizure : the Journal of the British Epilepsy Association·Torbjörn Tomson, Dina Battino
Jan 30, 2008·Cancer Treatment Reviews·Alfonso Duenas-GonzalezLuis A Herrera
Mar 12, 2008·The Journal of Trauma·Christian ShultsHasan B Alam
Jul 22, 2008·Critical Care : the Official Journal of the Critical Care Forum·Martin K AngeleIrshad H Chaudry
Jul 25, 2009·Surgery·Hasan B AlamGeorge C Velmahos
Sep 17, 2009·Biochemical Society Transactions·Nicole Terbach, Robin S B Williams
Dec 25, 2009·Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine·Tareq KheirbekHasan B Alam
Jun 19, 2010·The New England Journal of Medicine·Janneke JentinkUNKNOWN EUROCAT Antiepileptic Study Working Group

❮ Previous
Next ❯

Methods Mentioned

BETA
Assay
acetylation
histone acetylation

Related Concepts

Related Feeds

Bipolar Disorder

Bipolar disorder is characterized by manic and/or depressive episodes and associated with uncommon shifts in mood, activity levels, and energy. Discover the latest research this illness here.

Adherens Junctions

An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques). Adherens junctions uniquely disassemble in uterine epithelial cells to allow the blastocyst to penetrate between epithelial cells. Discover the latest research on adherens junctions here.

Cadherins and Catenins

Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells: alpha-catenin can bind to β-catenin and can also bind actin. β-catenin binds the cytoplasmic domain of some cadherins. Discover the latest research on cadherins and catenins here.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis