THE HDAC INHIBITOR VALPROIC ACID (VPA) REDUCES HEART DAMAGE OF THE SHR (SPONTANEOUSLY HYPERTENSIVE RAT) THROUGH EPIGENETIC CARDIAC-TRH MODULATION

AISICOVICH, M; GIARDINA GL; LANDA, MARIA S.; PERES DIAZ, LSE; GARCÍA, SI; SCHUMAN, ML; PIROLA, CARLOS JOSÉ

Rio de Janeiro

Congreso; World Congress of Cardiology; 2022

SOCIEDADE BRASILEIRA DE CARDIOLOGIA

Cardiac TRH (cTRH) induces cardiac damage and its inhibition attenuates heart injury indifferent models: SHR and cTRH overexpression (Schuman 2011,2014); Angiotensin II infusion and doxorrubicin cardiotoxicity (Peres Diaz 2018,2020) and LVH induced by obesity or leptin infusion (Aisicovich 2019,2021). We described that cTRH inhibition increase LVEF% and preserve cardiac function after acute MI in rats (Schuman 2021). Histone acetylation (HDACs) modulates gene expression by epigenetic alterations as DNA methylation. VPA, an FDA approved drug for bipolar disease and epilepsy, protects heart against MI injury (Tian 2019). As VPA is an inhibitor of HDACs, we hypothesized that inhibition of HDACs with VPA might attenuate LVH and fibrosis in SHR by the modulation of cTRH. 7 w-old male SHR and WKY received VPA and hearts were used after 10w of treatment. BP, LVH index and cTRH expression significantly increased in SHR. VPA slightly attenuated (p < 0.05) the higher SHR BP, without effect in WKY.LVH index decreased (p < 0.05) only in SHR. LVPWT significantly decreased (p < 0.05) only in SHR. As hypothesized, VPA normalized cTRH mRNA expression in SHR (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) and TRH IHQ confirmed these results (p < 0.05) which brought a strong reduction in fibrosis in LV, by decrease in BNP and 3-collagen expression in SHR+VPA. This was confirmed by Masson?s an d Sirius Red stainings (p < 0.01). SHR offspring born from VPA-treated parents with a 2-week washout period before mating, wich never received VPA, surprisingly had a significant decrease in hypertrophy (LVW/ BW) vs offspring of both SHR untreated parents, showing a transgenerational inheritance.Indeed, SHR showed a decrease in % TRH promoter methylation (Increase in gene expresion) that is significantly reverted in offspring of VPA treated parents (methylation-specific PCR). Consistently, we observed a decrease in cTRH expression (p < 0.05), and therefore, a significant reduction (p < 0.05) in BNP and type 3 Collagen expression, despite the high BP in VPA parents offsprin. To sum up, we described for the first time that VPA treatment modulates cTRH gene and consequently attenuates heart fibrosis and hypertrophy in the SHR, without affecting BP.We show an epigenetic modulation of VPA over cTRH promoter that could be responsible not only of cardiac alterations during VPA treatment, but beyond affecting next generation with results still unknown.