VALPROATE (VPA), A HISTONE DEACETYLASE (HDAC) INHIBITOR, DECREASES FIBROSIS IN THE HYPERTROPHYC HEART OF SHR: TRH GENE EXPRESSION

PERES DIAZ, LUDMILA S; LANDA, MARIA SILVINA; AISICOVICH MAIA; SCHUMAN, MARIANO LUIS; TOBLLI, J; GARCÍA SILVIA INES; PIROLA, CARLOS JOSE

Mar del Plata

Congreso; Sociedad Argentina de Investigación Clínica; 2017

SAIC

VALPROATE (VPA), A HISTONEDEACETYLASE (HDAC) INHIBITOR, DECREASES FIBROSIS IN THE HYPERTROPHYC HEART OFSHR: TRH GENE EXPRESSION  Peres Diaz, Ludmila S1,2, Landa,María S1,2,3; Aisicovich, Maia1,2; Schuman, Mariano L1,2 ; Toblli Jorge E3;García, Silvia I1,2,3 , Pirola, Carlos J 1,3.1 University of Buenos Aires-, Instituteof Medical Research A Lanari, Buenos Aires, Argentina. 2 National Scientific and TechnicalResearch Council (CONICET), University of Buenos Aires Laboratory of Molecular Cardiology,-Institute of Medical Research (IDIM), Buenos Aires, Argentina.   3 National Scientific and TechnicalResearch Council (CONICET), University of Buenos Aires Department of MolecularGenetics and Biology of Complex Diseases, Institute of Medical Research (IDIM), Buenos Aires, Argentina4Laboratory of Experimental Medicine, Htal Aleman, Buenos Aires. Cardiac TRH induceshypertrophy (LVH) and fibrosis in normal rats. Also, cardiac TRH system isoverexpressed in SHR. It´s known that the histone deacetylase families, which modifythe access of transcription factors to DNA, affect cardiac hypertrophy inanimal models. As VPA is an inhibitor of HDACs and modulates gene expressionthrough epigenetic alterations such as DNA methylation, we hypothesized thatinhibition of HDACs with VPA might attenuate LVH and the fibrotic process inSHR by modulating cardiac TRH gene expression. 7 w-old male SHR and WKY receivedVPA. Blood pressure (BP) was recorded; after 10w of treatment rats were euthanizedand hearts obtained. BP, LVH index and cTRH expression were increased in SHR vsWKY. VPA slightly attenuated (ANOVA,p<0.05) the higher BP (mmHg) seen inuntreated SHR, without effect in  WKY (WKY= C:128±4 vs VPA:126±3 and SHR=C220±4 vs VPA201±4). Hypertrophicindex (HW/BW*100) was reduced (p<0.05) only in SHR  (C:0.4516±0.02 vs VPA:0.3950±0.02). Byecocardiography we found a (p<0.05) reduction in LVPWT(mm) only in SHR(C:0.310±0.02 vs VPA:0.242±0.021). VPA normalizes (p<0.05) the higherexpression of BNP and type 3 collagen in the LV of  SHR indicating a strong reduction infibrosis. This effect was confirmed by Masson?s Trichrome and Sirius Redstainings (p<0.01). The higher TRH mRNA in SHR heart was reduce in the SHR+VPA to values similar to WKY (WKY,C:0.61±0.7vs VPA:0.41±0.97; SHR,C:5.72+0.9 vs VPA:0.61+0.9,p<0.05). Decreased TRH level by IHQ induced by HDAC inhibition confirms thisresult. Offspring born from VPA-treated parents with a 2-weeks washout periodbefore mating, and which did not receive VPA ever, had a reduction of hypertrophy,fibrosis and cardiacTRH expression showing transgenerational inheritance. We describedfor the first time that VPA reduces fibrosis in an independent manner of LVH,effects inherited by the next generation. Our results suggest that epigenetic TRHmodulation may play a role.