Valproate Decreases Transgenerationally Blood Pressure by Affecting Thyrotropin-releasing Hormone Promoter DNA Methylation and Gene Expression in Spontaneously Hypertensive Rat

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

MOLECULAR AND CELLULAR BIOCHEMISTRY

SPRINGER

Año: 2024

0300-8177

Central TRH, a neuropeptide,is involved in cardiovascular regulation. We demonstrated that the overexpressionof diencephalic TRH (dTRH) in SHR rats can be prevented by antisense treatment,normalizing blood pressure (BP). Valproate (VPA) is an inhibitor of histonedeacetylases (HDAC) which modulates gene expression through epigenetic modificationssuch as DNA methylation. Aims: Study the role of HDAC inhibition in theregulation of dTRH gene expression and its effect on the pathogenesis ofhypertension. Main methods: We treated 7-weeks-old male and female SHR and WKYrats with VPA for 10 weeks and evaluated BP, dTRH mRNA and methylation genestatus. Key findings: VPA attenuated the elevated BP and dTRH mRNA expression characteristicof SHR. Indeed, we found a significant 62% reduction in dTRH mRNA expression inthe SHR+VPA group compared to control SHR. The decrease TRH mRNA expression inducedby VPA was confirmed “in vitro” in a primary neuron culture using trichostatin A.With methylation specific PCR we demonstrated a significant increase in TRHpromoter DNA methylation level in SHR+VPA group compared to control SHR. Alsothere was a significant negative correlation between methylation status, dTRHmRNA expression, and blood pressure values. After 2 weeks of treatmentinterruption, rats were mated. Although they did not receive any treatment, theoffspring born from VPA-treated SHR parents showed similar changes in BP, dTRHexpression and methylation status, implying a transgenerational inheritance. Ourfindings suggest that dTRH modulation by epigenetics mechanism affects BP andcould be inherited by the next generation in SHR rats.