VALPROATE DECREASES TRAN GENERATIONALLY BLOOD PRESSURE BY AFFECTING TRH PROMOTER DNA METHYLATION AND GENE EXPRESSION IN SHR

LANDA, MARIA SILVINA; SCHUMAN, MARIANO LUIS; PEREZ DIAS, LUDMILA; AISICOVICH, MAIA; GIRONACCI, MARIELA; GARCIA, SILVIA INES; PIROLA, CARLOS JOSÉ

CABA

Congreso; XXIII Congreso Argentina de Hipertension Arterial; 2016

In the central nervous system, TRH acts asneurotransmitter involved in cardiovascular regulation. We demonstrated thatthe overexpression of diencephalic TRH (dTRH) in SHR rats could be reverted byantisense treatment normalizing the blood pressure (BP). Valpoate (VPA), aninhibitor of histone deacetylases, can modulate gene expression throughepigenetic alterations such as DNA methylation. Here, to study the role of HDACinhibition in the regulation of the TRH expression and its effect on thepathogenesis of hypertension, we treated seven weeks old male SHR and WKY with VPA.Blood pressure was recorded weekly; following 10 weeks of treatment rats wereeuthanized. BP and dTRH expression were increased in SHR vs WKY. VPA attenuatedthe higher blood pressure seen in untreated SHR, without effect in WKY strain.Changes in blood pressures were paired with alterations in the dTRH mRNAexpression. Indeed we found a significant 62 % reduction in the abundance ofdTRH mRNA of the SHR+VPA group compared to SHR control group. Decreased TRHmRNAinduced by HDAC inhibition was confirm ?in vitro? by neuron primary cultureusing TSA. We performed methylation specific PCR and demonstrated a significantincrease of the DNA methylated level in SHR+VPA group compared to SHR control anda significant negative correlation between methylation status and dTRH mRNAexpression. Another group of male and female SHR and WKY were treated with VPA asdescribed. After 2 weeks of the treatment interruption, rats were mated. Offspringborn from VPA treated parents did not receive VPA ever. We observed that changesin BP, TRH expression and methyaltion status were reproduced in offspring showinga transgenerational inheritance. Thus, these results suggest that TRHmodulation by epigenetics mechanism may affect BP and could be inherited by thenext generation in SHR rats.