Analysis of the Specific Role of Histone Deacetylase 2 (HDAC2) for Atrial Remodeling in Atrial Fibrillation

组蛋白脱乙酰酶 2 (HDAC2) 在心房颤动心房重构中的具体作用分析

• 批准号: 460291259
• 负责人: Dr. Jan Sebastian Schulte
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/460291259?language=en
• 关键词: Analysis; Specific; Role; Histone; Deacetylase

Atrial fibrillation is the most common persistent arrhythmia in the elderly and increases the risk of stroke, heart failure, hospitalization and death. Structural and functional remodeling processes, which are summarized under the term "atrial remodeling", play a central role in the development and, above all, the chronification of this rhythm disorder. To date, no effective therapy exists that could stop the development of atrial remodeling in atrial fibrillation. We recently showed that the anticonvulsant valproic acid, which has been used for decades, delays atrial remodeling and the development of atrial fibrillation in mice with myocardial expression of the repressor CREM (cAMP responsive element modulator) isoform IbΔC-X. CREM-IbΔC-X-transgenic mice are a well-described mouse model with extensive atrial remodeling associated with spontaneous onset of atrial fibrillation. In this model, valproic acid reduced the development of characteristic components of atrial remodeling that are also present in other animal models of atrial fibrillation and in patients with atrial fibrillation. Valproic acid acts as an inhibitor of histone deacetylases (HDACs) and inhibits the HDAC isoforms 1, 2, 3 and 8 in therapeutic doses. The overall aim of the project is to investigate the individual functional significance of these HDAC isoforms for atrial remodeling associated with atrial fibrillation. Since there are no specific inhibitors for these individual isoforms so far, we will investigate the effect of genetically switching off these isoforms in CREM-IbΔC-X-transgenic mice by crossing them with corresponding "knockout" mice. The focus of the work program is on the HDAC2 isoform, since we have already shown that the knockout of this one HDAC isoform leads to a reduced expression of ultrastructural changes in atria of CREM-IbΔC-X-transgenic mice. In the context of this proposal, we will comprehensively investigate which components of structural and functional remodelling are affected by the elimination of HDAC2 in CREM-IbΔC-X-transgenic mice and whether the elimination of HDAC2 is ultimately sufficient to delay the development of atrial fibrillation. In the form of key experiments, the analysis will be extended to the isoforms 1, 3 and 8. Thus, the aim is to identify an optimal profile of HDAC inhibition by precise mapping of the effects of these HDACs, which positively influences as many components of atrial remodeling as possible and slows down the development of atrial fibrillation.

房颤是老年人最常见的持续性心律失常，增加了中风、心力衰竭、住院和死亡的风险。结构和功能重构过程被概括为“心房重构”，在这种节律紊乱的发展和最重要的时代化过程中发挥着核心作用。到目前为止，还没有有效的治疗方法可以阻止房颤患者心房重构的发展。我们最近发现，已经使用了几十年的抗惊厥剂丙戊酸可以延缓心肌抑制因子CREM(cAMP反应元件调节剂)亚型IbΔC-X表达的小鼠心房重构和心房颤动的发展。CREM-IbΔC-X转基因小鼠是一种广为人知的与自发性心房颤动发作相关的心房重构的小鼠模型。在这个模型中，丙戊酸减少了心房重构的特征成分的发展，这些成分也存在于其他房颤动物模型和房颤患者中。丙戊酸作为组蛋白脱乙酰酶(HDAC)的抑制剂，在治疗剂量下抑制HDAC亚型1、2、3和8。该项目的总体目标是调查这些HDAC亚型在房颤相关的心房重塑中的个体功能意义。由于到目前为止还没有针对这些个别亚型的特异性抑制剂，我们将通过将这些亚型与相应的“基因敲除”小鼠杂交，来研究在CREM-IbΔC-X转基因小鼠中从基因上关闭这些亚型的效果。工作计划的重点是HDAC2亚型，因为我们已经证明，敲除这种HDAC2亚型会导致CREM-IbΔC-X转基因小鼠心房超微结构变化的表达减少。在这项建议的背景下，我们将全面调查在CREM-IbΔC-X转基因小鼠中，hdac2的消除对结构和功能重构的哪些组成部分产生影响，以及hdac2的消除是否最终足以延缓房颤的发展。在关键实验的形式下，分析将扩展到异构体1、3和8。因此，目的是通过精确定位这些HDAC的作用来确定抑制HDAC的最佳图谱，从而对尽可能多的心房重构成分产生积极影响，并减缓心房颤动的发展。