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

Zuckermann, AM; La Ragione, RM; Baines, DL; Williams, RS (2015) Valproic acid protects against haemorrhagic shock-induced signalling changes via PPARγ activation in an in vitro model. British Journal of Pharmacology, 172 (22). pp. 5306-5317.
SGUL Authors: Baines, Deborah

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BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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) inhibitory activity. Specific pharmacological inhibition (by T0070907) or knockdown of PPARγ blocked the protective effect of VPA against these signalling changes and apoptosis. In addition, specific activation of PPARγ using ciglitazone reproduced the changes induced by VPA in haemorrhagic shock-like conditions. CONCLUSION AND IMPLICATIONS: Changes in GSK3β-Ser(9) phosphorylation in in vivo haemorrhagic shock models can be modelled in vitro, and this has identified a role for PPARγ activation in the protective role of VPA.

Item Type: Article
Additional Information: © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproductioninany medium, provided the original work is properly cited and is not used for commercial purposes.
Keywords: Pharmacology & Pharmacy, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: British Journal of Pharmacology
Language: eng
22 October 2015Published
Publisher License: Creative Commons: Attribution-Noncommercial 4.0
Project IDFunderFunder ID
MR/K012770/1Medical Research Council
PubMed ID: 26333042
Web of Science ID: WOS:000365403200007
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