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

ABSTRACT: 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 GSK3?-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 GSK3?-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 GSK3?-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 ?-catenin degradation while increasing histone 2/3 acetylation. This effect was reproduced by several VPA-related compounds with known PPAR? agonist activity, independent of histone deacetylase (HDAC) inhibitory activity. Specific pharmacological inhibition (by T0070907) or knockdown of PPAR? blocked the protective effect of VPA against these signalling changes and apoptosis. In addition, specific activation of PPAR? using ciglitazone reproduced the changes induced by VPA in haemorrhagic shock-like conditions. CONCLUSION AND IMPLICATIONS:Changes in GSK3?-Ser(9) phosphorylation in in vivo haemorrhagic shock models can be modelled in vitro, and this has identified a role for PPAR? activation in the protective role of VPA.

SUBMITTER: Zuckermann AM

PROVIDER: S-EPMC5123713 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Zuckermann Alexandra M E AM La Ragione Roberto M RM Baines Deborah L DL Williams Robin S B RS

British journal of pharmacology 20151022 22

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>The ...[more]

PMID: 26333042

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Project description:PurposeOestrogen receptor β is believed to exert a cardioprotective effect against ischaemic injury. Nonetheless, the mechanism underlying its protective action remains to be fully elucidated. Recently, increased attention has been focused on Notch1 signalling for ameliorating cardiac ischaemic injury. Here, we hypothesised that oestrogen receptor β activation attenuates myocardial infarction (MI)-induced cardiac damage by modulating the Notch1 signalling pathway.MethodsMale C57BL/6 mice were used to establish an MI model through the ligation of the anterior descending branch of the left coronary artery. Two chemical drugs, 2,3-Bis(4-hydroxyphenyl)-propionitrile (DPN) and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-s-phenylglycine t-butyl ester (DAPT), a specific inhibitor of Notch1 signalling) were administered via intraperitoneal injection to change oestrogen receptor β and Notch1 activities. Immunohistochemistry, western blot analysis, enzyme-linked immunosorbent assay (Elisa) assessment and echocardiography were used in this study to analyse cardiac oxidative stress, apoptosis, infraction volume, fibrosis and cardiac function.ResultsDPN-mediated oestrogen receptor β activation effectively protected cardiomyocytes from MI-induced oxidative damage and apoptosis. Furthermore, oestrogen receptor β activation reduced the infarct size and lowered the levels of myocardial enzymes in the serum, thereby leading to greater overall cardiac function improvement. Ischaemic injury-induced myocardial fibrosis was attenuated by oestrogen receptor β activation. Nevertheless, all of these cardioprotective effects of oestrogen receptor β activation were almost abrogated by DAPT administration, i.e. DAPT attenuated the anti-oxidative and anti-apoptotic effects and the decrease in infarct and fibrotic areas and reversed cardiac functional recovery. The levels of phospho-phosphatidylinositol-3-kinase (PI3K) and phospho-protein kinase B (Akt) were increased after DPN administration, and this change was reversed after DAPT was administered.ConclusionsAll of these new findings indicate that oestrogen receptor β activation is effective in ameliorating MI-induced cardiac dysfunction by enhancing Notch1 signalling and that PI3K/Akt signalling is the downstream mediator.

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

Publications

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

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