Landa María S, Schuman Mariano L, Aisicovich Maia, Peres Diaz Ludmila S, Gironacci Mariela M, García Silvia I, Pirola Carlos J
School of Medicine, Institute of Medical Research A. Lanari, Universidad de Buenos Aires, Combatientes de Malvinas 3150, 1427, Ciudad Autonoma de Buenos Aires, Argentina.
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.
Mol Cell Biochem. 2025 Feb;480(2):937-949. doi: 10.1007/s11010-024-05001-4. Epub 2024 Apr 17.
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.
Study the role of HDAC inhibition in the regulation of dTRH gene expression and its effect on the pathogenesis of hypertension.
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.
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.
中枢促甲状腺激素释放激素（TRH），一种神经肽，参与心血管调节。我们证明，反义治疗可预防自发性高血压大鼠（SHR）中脑间TRH（dTRH）的过表达，使血压正常化。丙戊酸盐（VPA）是组蛋白脱乙酰酶（HDAC）的抑制剂，其通过DNA甲基化等表观遗传修饰来调节基因表达。
研究HDAC抑制在dTRH基因表达调控中的作用及其对高血压发病机制的影响。
我们用VPA对7周龄的雄性和雌性SHR大鼠及Wistar-Kyoto大鼠（WKY）进行10周治疗，并评估血压、dTRH mRNA和甲基化基因状态。
VPA减轻了SHR特有的血压升高和dTRH mRNA表达。事实上，我们发现与对照SHR相比，SHR + VPA组中dTRH mRNA表达显著降低了62%。使用曲古抑菌素A在原代神经元培养中“体外”证实了VPA诱导的TRH mRNA表达降低。通过甲基化特异性PCR，我们证明与对照SHR相比SHR + VPA组中TRH启动子DNA甲基化水平显著增加。治疗中断2周后，大鼠进行交配。尽管它们没有接受任何治疗，但VPA处理的SHR亲本所生的后代在血压、dTRH表达和甲基化状态方面表现出相似的变化，这意味着存在跨代遗传。我们的研究结果表明，表观遗传机制对dTRH的调节会影响血压，并且可能在SHR大鼠中遗传给下一代。
