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Valproate decreases transgenerationally blood pressure by affecting thyrotropin-releasing hormone promoter DNA methylation and gene expression in spontaneously hypertensive rat

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Abstract

Central TRH, a neuropeptide, is involved in cardiovascular regulation. We demonstrated that the overexpression of diencephalic TRH (dTRH) in SHR rats can be prevented by antisense treatment, normalizing blood pressure (BP). Valproate (VPA) is an inhibitor of histone deacetylases (HDAC) which modulates gene expression through epigenetic modifications such as DNA methylation. Aims: Study the role of HDAC inhibition in the regulation of dTRH gene expression and its effect on the pathogenesis of hypertension. Main methods: We treated 7-weeks-old male and female SHR and WKY rats with VPA for 10 weeks and evaluated BP, dTRH mRNA and methylation gene status. Key findings: VPA attenuated the elevated BP and dTRH mRNA expression characteristic of SHR. Indeed, we found a significant 62% reduction in dTRH mRNA expression in the SHR + VPA group compared to control SHR. The decrease TRH mRNA expression induced by VPA was confirmed “in vitro” in a primary neuron culture using trichostatin A. With methylation specific PCR we demonstrated a significant increase in TRH promoter DNA methylation level in SHR + VPA group compared to control SHR. After 2 weeks of treatment interruption, rats were mated. Although they did not receive any treatment, the offspring born from VPA-treated SHR parents showed similar changes in BP, dTRH expression and methylation status, implying a transgenerational inheritance. Our findings suggest that dTRH modulation by epigenetics mechanism affects BP and could be inherited by the next generation in SHR rats.

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Acknowledgements

The authors thank Noelia Gonzales Mansilla (Institute of Medical Research A. Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina) for the technical assistance.

Funding

This work was supported by Grants PICT 2010-2581, PICT 2010-0441 (Agencia Nacional de Promoción Cientifica y Tecnologica), PIP 11220090100636 (Consejo Nacional de Investigaciones Científicas y Tecnicas) and PIP 11220200103056CO (Consejo Nacional de Investigaciones Científicas y Tecnicas).

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Authors and Affiliations

  1. School of Medicine, Institute of Medical Research A. Lanari, Universidad de Buenos Aires, Combatientes de Malvinas 3150, 1427, Ciudad Autonoma de Buenos Aires, Argentina

    María S. Landa, Mariano L. Schuman, Maia Aisicovich, Ludmila S. Peres Diaz & Silvia I. García

  2. Department of Molecular Cardiology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autonoma de Buenos Aires, Argentina

    María S. Landa, Mariano L. Schuman, Maia Aisicovich, Ludmila S. Peres Diaz & Silvia I. García

  3. Department of Molecular Genetics and Biology of Complex Diseases, Center for Traslational Research in Health, Maimonides University, Hidalgo 775, 1405, Ciudad Autonoma de Buenos Aires, Argentina

    Carlos J. Pirola

  4. National Scientific and Technical Research Council (CONICET), Ciudad Autonoma de Buenos Aires, Argentina

    Carlos J. Pirola

  5. Laboratory of Experimental Medicine, Hospital Alemán, Ciudad Autónoma de Buenos Aires, Argentina

    Silvia I. García

  6. Department of Biological Chemistry, Faculty of Pharmacy and Biochemistry, School of Pharmacy and Biochemistry (IQUIFIB), National Scientific and Technical Research Council (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autonoma de Buenos Aires, Argentina

    Mariela M. Gironacci

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  1. María S. Landa
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Contributions

MSL, MLS, LSPD, MA, MMG, SIG analyzed data; MSL, SIG and CJP interpreted results of experiments; MSL, MLS, prepared figures; MSL, SIG and CJP drafted manuscript; MSL, MLS, SIG and CJP edited and revised manuscript and approved final version of manuscript; MSL, MLS, LSPD, MA and MMG performed experiments; CJP conception and design of research.

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Correspondence to Silvia I. García or Carlos J. Pirola.

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Landa, M.S., Schuman, M.L., Aisicovich, M. et al. Valproate decreases transgenerationally blood pressure by affecting thyrotropin-releasing hormone promoter DNA methylation and gene expression in spontaneously hypertensive rat. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-05001-4

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