Valproate (VPA), a Histone Deacetylase (HDAC) Inhibitor, Decreases Fibrosis in the Hypertrophyc Heart os SHR: TRH Gene Expression

PERES DIAZ LUDMILA; MARÍA S. LANDA; MAIA AISICOVICH; MARIANO L. SCHUMAN; JORGE E TOBLLI; SILVIA INES GARCIA; CARLOS J. PIROLA

Buenos Aires

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA

Cardiac TRH induces hypertrophy (LVH) and fibrosis in normal rats. Also, cardiac TRH system is overexpressed in SHR. It´s known that the histone deacetylase families, which modify the access of transcription factors to DNA, affect cardiac hypertrophy in animalmodels. As VPA is an inhibitor of HDACs and modulates gene ex- pression through epigenetic alterations such as DNA methylation, we hypothesized that inhibition of HDACs with VPA might attenuate LVH and the fibrotic process in SHR by modulating cardiac TRH gene expression. 7 w-old male SHR and WKY received VPA. Blood pressure (BP) was recorded; after 10w of treatment rats were euthanized and hearts obtained. BP, LVH index and cTRH expression were increased in SHR vs WKY. VPA slightly attenuated (ANOVA,p<0.05) the higher BP (mmHg) seen in untreated SHR, without effect in WKY (WKY= C:128±4 vs VPA:126±3 and SHR=C220±4 vs VPA201±4). Hypertrophic index (HW/BW*100) was reduced (p<0.05) only in SHR (C:0.4516±0.02 vs VPA:0.3950±0.02). By ecocardiography 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 higher expression of BNP and type 3 collagen in the LV of SHR indicating a strong reduction in fibrosis. This effect was confirmed by Masson?s Trichrome and Sirius Red stainings (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 this result. Offspringborn from VPA-treated parents with a 2-weeks washout period before mating, and which did not receive VPA ever, had a reduction of hypertrophy, fibrosis and cardiacTRH expression showing transgenerational inheritance. We described for the first time that VPA reduces fibrosis in an independent manner of LVH, effects inherited by the next generation. Our results strongly suggest that epigenetic TRH modulation may play a role.