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

MARIA S LANDA; MAIA AISICOVICH; CARLOS J PIROLA; LUDMILA S PERES DIAZ; SILVIA I GARCÍA; MARIANO L SCHUMAN; MARIELA M. GIRONACCI

CABA

Congreso; XXIII Congreso de la Sociedad Argentina de Hipertensión Arterial; 2016

Sociedad Argentina de Hipertensión Arterial-International Society of Hypertension

In the central nervous system, TRH acts as neurotransmitter involved in cardiovascular regulation. We demonstrated that the overexpression of diencephalic TRH (dTRH) in SHR rats could be reverted by antisense treatment normalizing the blood pressure (BP). Valpoate (VPA), an inhibitor of histone deacetylases, can modulate gene expression through epigenetic alterations such as DNA methylation. Here, to study the role of HDAC inhibition in the regulation of the TRH expression and its effect on the pathogenesis of hypertension, we treated seven weeks old male SHR and WKY with VPA. Blood pressure was recorded weekly; following 10 weeks of treatment rats were euthanized. BP and dTRH expression were increased in SHR vs WKY. VPA attenuated the higher blood pressure seen in untreated SHR, without effect in WKY strain. Changes in blood pressures were paired with alterations in the dTRH mRNA expression. Indeed we found a significant 62 % reduction in the abundance of dTRH mRNA of the SHR+VPA group compared to SHR control group. Decreased TRHmRNA induced by HDAC inhibition was confirm ?in vitro? by neuron primary culture using TSA. We performed methylation specific PCR and demonstrated a significant increase of the DNA methylated level in SHR+VPA group compared to SHR control and a significant negative correlation between methylation status and dTRH mRNA expression. Another group of male and female SHR and WKY were treated with VPA as described. After 2 weeks of the treatment interruption, rats were mated. Offspring born from VPA treated parents did not receive VPA ever. We observed that changes in BP, TRH expression and methyaltion status were reproduced in offspring showing a transgenerational inheritance. Thus, these results suggest that TRH modulation by epigenetics mechanism may affect BP and could be inherited by the next generation in SHR rats.