CHRONIC ADMINISTRATION OF VALPROIC ACID INHIBITS COMPLETE ACTIVATION OF HEPATIC STELLATE CELLS IN VITRO AND IN VIVO.

Inge Mannaerts, Andrea Noetel, Margarete Odenthal, Albert Geerts, Leonardus Van Grunsven

Onderzoeksoutput: Meeting abstract (Book)Research

Samenvatting

Background and aims Hepatic stellate cell (HSC) activation is a critical step in the pathogenesis of liver fibrosis. Stellate cell activation leads to a phenotypic transdifferentiation characterized by loss of vitamin A and extensive production of extracellular matrix. The clarification of this process is important for the development of effective therapies for fibrosis. The use of the histone deacetylase inhibitor trichostatin A in HSC cultures has shown that histone deacetylases might play a role in the pathogenesis of liver fibrosis. Here, we evaluated the effect of a histone deacetylase inhibitor, valproic acid (VPA), on mouse HSC transdifferentiation in vitro and in vivo.
Methods & Results The exposure of freshly isolated HSCs to 2.5mM VPA inhibited morphological changes and cell proliferation. Expression of HSC activation markers analyzed by qPCR and western blot showed that VPA-treatment inhibited the induction of activation markers like Acta2, Lox, Spp1 and Myh11. Treatment of mice with VPA decreased collagen deposition and in vivo activation of HSCs in the liver of CCl4-treated mice, in a prophylactic and therapeutic set-up. Class I histone deacetylase silencing through RNA interference in mouse HSCs could only partially mimic the treatment with VPA.
Conclusions We hypothesize that the VPA-effect partially results from class I histone deacetylase inhibition, but that also non-histone deacetylase class I VPA targets are involved in the HSC activation process. We are currently analyzing the gene expression and miRNA profile of control and VPA treated cells, using respectively the mouse GeneChip Mouse Gene 1.0 ST Array (Affimetrix) and the TaqMan Rodent MicroRNA Array v2.0 (Applied Biosystems) in order to further identify VPA targets that play a role during HSC activation.
Originele taal-2English
TitelUnknown
StatusPublished - 17 feb 2010
EvenementUnknown - Stockholm, Sweden
Duur: 21 sep 200925 sep 2009

Conference

ConferenceUnknown
LandSweden
StadStockholm
Periode21/09/0925/09/09

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