Valproate decreases trangenerationally blood pressure by affecting TRH promoter DNA methylation and gene expression in SHR

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

CABA

Congreso; Latin Section of the Interamerican Society of Hypertension, Congreso XXII de la Sociedad Argentina de Hipertension Arterial; 2016

Sociedad Argentina de Hipertension Arterial (SAHA)

VALPROATE DECREASES TRAN GENERATIONALLY BLOOD PRESSUREBY AFFECTING TRH PROMOTER DNA METHYLATION AND GENE EXPRESSION IN SHR   Landa, María S1,2; Schuman,Mariano L2.; Peres Diaz, Ludmila S2; Aisicovich, Maia2;Gironacci, M.3;  García,Silvia I.2; Pirola, Carlos J.1   1Departmentof Molecular Genetics and Biology of Complex Diseases, Institute of MedicalResearch A Lanari-IDIM, University of Buenos Aires-National Scientific andTechnical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina2 Laboratoryof Molecular Cardiology, Institute of Medical Research A Lanari-IDIM,University of Buenos Aires-National Scientific and Technical Research Council(CONICET), Ciudad Autónoma de Buenos Aires, Argentina.3Departamento de Química Biológica, IQUIFIB-CONICET,Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires,Argentina In the centralnervous system, TRH acts as neurotransmitter involved in cardiovascularregulation. We demonstrated that the overexpression of diencephalic TRH (dTRH)in SHR rats could be reverted by antisense treatment normalizing the bloodpressure (BP). Valpoate (VPA), an inhibitor of histone deacetylases, canmodulate gene expression through epigenetic alterations such as DNAmethylation. Here, to study the role of HDAC inhibition in the regulation ofthe TRH expression and its effect on the pathogenesis of hypertension, wetreated seven weeks old male SHR and WKY with VPA. Blood pressure was recordedweekly; following 10 weeks of treatment rats were euthanized. BP and dTRHexpression were increased in SHR vs WKY. VPA attenuated the higher bloodpressure seen in untreated SHR, without effect in WKY strain. Changes in bloodpressures were paired with alterations in the dTRH mRNA expression. Indeed wefound a significant 62 % reduction in the abundance of dTRH mRNA of the SHR+VPAgroup compared to SHR control group. Decreased TRHmRNA induced by HDACinhibition was confirm ?in vitro? by neuron primary culture using TSA. Weperformed methylation specific PCR and demonstrated a significant increase ofthe DNA methylated level in SHR+VPA group compared to SHR control and asignificant 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.