Sirt5介导PDH琥珀酰化修饰调控心房肌细胞糖代谢在心房颤动中的作用及机制

Atrial glucose metabolism is dysregulated in atrial fibrillation (AF), but its precise molecular mechanism and its role in the progression of atrial fibrillation still remain unclear. Recent studies have reported that succinylation plays an important role to regulate cellular glucose metabolism. We previously found that: (1) The level of succinylated PDH, the essential enzyme to glucose metabolism, markedly increased in atrial tissues of AF patients accompanied with the downregulation of Sirt5, the key factor of succinylation. (2) Overexpression of Sirt5 could prevent tachypacing-induced PDH succinylation, improve glucose metabolism and inhibit apoptosis and ion channel dysregulation in atrial myocytes. Therefore, we hypothesize that downregulation of Sirt5 could induce PDH succinylation and suppress its activity, which promotes dysregulation of glucose metabolism resulting in atrial electrical and structural remodeling and the occurrence and persistence of AF. We will use the metabonomics, comprehensive techniques of bioinformational and functional biology to elucidate the role and mechanism of Sirt5-mediated succinylation in atrial abnormal glucose metabolism and progression of atrial fibrillation, by targeting regulation of PDH. Our study will provide the new insights into the potential function of succinylation in regulating atrial metabolic remodeling, and supply novel targets for prevention and treatment.

心房颤动（房颤）时存在心房肌糖代谢异常，但其确切发生机制及在房颤发生并持续中的具体作用尚不清楚。新近研究报道，琥珀酰化修饰在调节细胞糖代谢中发挥重要生物学效应。我们前期发现：（1）房颤患者心房组织糖代谢调节关键酶PDH琥珀酰化修饰显著增加，琥珀酰化修饰调控核心因子Sirt5表达明显下调；（2）过表达Sirt5可阻止高频电刺激诱导的心房肌细胞PDH琥珀酰化修饰增加，改善糖代谢异常，防止细胞凋亡及离子通道改变。我们提出假设：心房肌细胞Sirt5表达降低，通过上调PDH琥珀酰化修饰水平抑制其活性，导致糖代谢紊乱，引起心房电和结构重构，促进房颤发生。本项目将运用代谢组学、生物信息学和功能学等方法，阐明Sirt5靶向调控PDH琥珀酰化修饰，在心房肌细胞糖代谢异常和房颤发生并持续中的重要作用及分子机制。本研究将从琥珀酰化修饰环节揭示心房代谢重构新机制，寻找防治新靶点。

本项目探讨新兴蛋白质酰化修饰即琥珀酰化修饰，在心房颤动（房颤）发生发展中的作用及其可能的分子机制。本项目拟探讨心房颤动时心房肌细胞Sirt5表达降低，促进PDH琥珀酰化修饰水平增加，从而抑制其活性，导致心房肌细胞糖代谢异常，引起心房电和结构重构，促进房颤发生。本项目应用转基因动物和原代心房肌细胞模型，阐明Sirt5介导的PDH 琥珀酰化修饰通过调控心房肌细胞糖代谢，在心房重构和房颤发生中的重要作用；揭示Sirt5靶向调控PDH琥珀酰化修饰，影响其活性的确切可能机制。本研究发现，房颤患者心房组织琥珀酰化修饰水平明显增加；在不同类型的房颤动物模型也检测到其修饰水平的升高。本项目结果证实，调控去琥珀酰化修饰的关键酶Sirt5是参与房颤发生发展的关键分子。上调Sirt5能够影响心房肌细胞糖代谢，改善钙离子通道活性，防止心房电重构，进而有效减少房颤的发生。细胞水平证实Sirt5介导的PDH琥珀酰化修饰，通过调控糖代谢影响心房肌细胞生物学特性。本项目结果证实，调控去琥珀酰化修饰的Sirt5是参与心房颤动发生发展的关键分子。