PFKM表达和乙酰化修饰调控心肌糖酵解能量代谢对房颤的影响及机制研究

心房颤动（房颤）是临床上最常见的持续性心律失常，其发病机制未完全阐明；我们前期研究发现肌肉型磷酸果糖激酶（PFKM）（糖酵解限速酶）等517个与心肌能量代谢相关的蛋白质在房颤患者心肌中差异表达，且PFKM乙酰化水平显著上调。已知乙酰化修饰是细胞内调控蛋白质活性的关键因素，而磷酸化修饰能影响蛋白质乙酰化水平。据此我们提出假说：PFKM受乙酰化修饰调控，通过差异表达调节心肌糖酵解代谢途径影响房颤发生发展；磷酸化修饰则调控PFKM乙酰化水平影响PFKM表达。本研究拟构建PFKM野生型/乙酰化位点突变型病毒，在犬房颤和原代心肌细胞模型上：①研究PFKM的表达及乙酰化修饰对能量代谢的影响，②明确房颤时PFKM乙酰化调节位点及磷酸化修饰对其乙酰化水平的影响，以期阐明PFKM及其乙酰化修饰调控房颤患者心肌能量代谢受损的机制，为房颤的防治提供新的理论依据和靶点。

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet molecular mechanisms of AF incidence and development remain largely unknown. In the preliminary study, we found that 517 differential expressed proteins including PFKM (phosphofructokinase, muscle type), the rate-limiting enzyme of glycolysis process, were differently expressed in atrial tissue of AF patients, and the acetylation level of PFKM was also higher in those patients. It has been identified that acetylation of proteins was the critical factor of regulating cellular biological activity, and could be effected by phosphorylation. Thus, we suppose that PFKM would be regulated by acetylation, and would regulate myocardial energy metabolism of glycolysis through the modification of expression and acetylation, and then influence AF incidence and persistence. Phosphorylation may effects the expression level of acetylation of PFKM. In this project, we will construct wild-type and mutated PFKM over-expression viruses to investigate their effects on glycolysis, energy metabolism and AF incidence and persistence. Moreover, the acetylation sites of PFKM and the effects of phosphorylation on PFKM acetylation will be defined on canine model and primary cardiac myocyte. This project is likely to illustrate the influence of PFKM expression and acetylation modification on regulating energy metabolism during AF, which may contribute to new theoretical basis and therapeutic targets for AF prevention and treatment.