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

房颤是老年人最常见的持续性心律失常，并增加中风、心力衰竭、住院和死亡的风险。结构和功能重构过程，概括为“心房重构”，在这种节律障碍的发展和最重要的是，慢性化中起着核心作用。到目前为止，还没有有效的治疗方法可以阻止心房重构的发展。我们最近发现，已经使用了几十年的抗惊厥药丙戊酸，延缓了抑制因子CREM （cAMP反应元件调节剂）异构体IbΔC-X心肌表达的小鼠心房重构和房颤的发展。CREM-IbΔC-X-transgenic小鼠是一种描述良好的小鼠模型，具有与自发性房颤发作相关的广泛心房重构。在该模型中，丙戊酸减少了房颤重构特征成分的发展，这些特征成分也存在于其他房颤动物模型和房颤患者中。丙戊酸作为组蛋白去乙酰化酶（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研究这些HDAC异构体在房颤相关心房重构中的个体功能意义。由于到目前为止还没有针对这些个体同种异构体的特异性抑制剂，我们将通过将CREM-IbΔC-X-transgenic小鼠与相应的“敲除”小鼠杂交来研究基因关闭这些同种异构体的影响。工作计划的重点是HDAC2异构体，因为我们已经证明，敲除这个HDAC异构体导致CREM-IbΔC-X-transgenic小鼠心房超微结构变化的表达减少。在本提案的背景下，我们将全面研究CREM-IbΔC-X-transgenic小鼠中HDAC2的消除对结构和功能重构的哪些组成部分的影响，以及HDAC2的消除是否最终足以延缓房颤的发展。以重点实验的形式，将分析扩展到同工异构体1、3和8。因此，目的是通过精确定位这些HDAC的作用来确定HDAC抑制的最佳概况，HDAC抑制尽可能多地积极影响心房重构的组成部分，并减缓房颤的发展。

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.