FHF2对肥厚心肌钙致钙释放的影响及其机制研究

The dysfunction of calcium induced calcium release (CICR) is one of the important characteristics of myocardial hypertrophy. Recent studies have shown that knockout of fibroblast growth factor homologous factor 2 (FHF2) significantly ameliorates myocardial hypertrophy. However, it is still unclear whether this effect is related to the process of CICR. Previous studies have demonstrated that FHF2 interacts directly with myocardial Junctophilin-2 (JP2) and modulates cardiac calcium currents. Knockdown of JP2 can cause serious disorder of CICR and induce cardiac hypertrophy by affecting the activity of Ryanodine Receptor (RyR) in sarcoplasmic reticulum. Our recent study found that knockout of FHF2 attenuated the decrease of JP2 expression in hypertrophic myocardium. Based on our own and others studies, we propose the following hypothesis: FHF2 is a key regulating protein of CICR in hypertrophic myocardium. Knockout of FHF2 may play a role in the regulation of CICR by affecting L-type calcium channel, RyR, dyad structure remodeling and JP2. In this project, we will use inducible cardiomyocyte-restricted FHF2 knockout mice in combination with multiple techniques to reveal the roles and mechanisms of FHF2 in CICR regulation. This study will provide new insights for the understanding of the mechanisms of cardiac hypertrophy development, and provide an important target for the further development of anti-cardiac hypertrophy drugs.

心肌钙致钙释放（CICR）失调是肥厚心肌的重要特征之一。最近研究发现敲除成纤维细胞生长因子同源性因子2（FHF2）具有显著抗心肌肥厚作用，但其机制是否与CICR环节有关并不清楚。前期研究证明FHF2可与心肌Junctophilin-2（JP2）相互作用，并影响心肌钙电流；敲低JP2可通过影响肌浆网兰尼定受体(RyR)的活性造成CICR失调并诱发心肌肥厚。申请人最近发现敲除FHF2可减弱肥厚心肌JP2表达的降低。结合申请人及他人的前期工作，提出如下假设：FHF2是肥厚心肌CICR调控关键蛋白，敲除FHF2可能通过影响L-型钙通道、RyR、二联体膜耦联结构的重构和JP2等环节而发挥对CICR的调控作用，本课题将利用FHF2心肌条件性敲除小鼠并结合多种实验技术，意图阐明FHF2在肥厚心肌CICR调控中的作用及其机制，该研究将为心肌肥厚发生机制提供新思路，并为深入开发抗心肌肥厚药物提供重要的靶点。

心肌钙致钙释放（CICR）机制的失调是心肌肥厚时的重要特征之一。本课题将利用FHF2心肌条件性敲除小鼠并结合多种技术，阐明FHF2在肥厚心肌CICR调控中的作用及其机制。课题组的前期研究已证明，FHF2（=FGF13）可与心肌Junctophilin-2（JP2）相互作用，并影响心肌钙电流；敲低JP2可通过影响肌浆网Ryanodine Receptor (RyR)的活性造成CICR失调并诱发心肌肥厚。本项目在历时3年的研究中发现：1.心肌特异性敲除FHF2小鼠可以改善心衰引起的心功能下降；2.心肌特异性敲除FHF2会通过减轻钙信号的异常，从而改善心衰时心脏功能的下降；3.心肌特异性敲除FHF2可减轻心衰引起的Cav1.2和 Serca2a含量下降和分布异常；4.心肌特异性敲除FHF2可减轻心衰引起的微管致密化而影响心肌细胞上Cav1.2和 Serca2a的功能，从而改善心衰时心脏钙信号紊乱；5.FHF2通过稳定微管的作用会加重心衰时心肌细胞钙信号异常，以及Serca2a功能的下降。因此，我们得出结论：敲除成纤维细胞生长因子同源性因子2（FHF2）具有显著的抗心肌肥厚作用，其机制与影响CICR环节密切相关。FHF2是肥厚心肌CICR调控蛋白，敲除FHF2可能通过影响L-型钙通道、RyR、二联体膜耦联结构的重构和JP2等环节而发挥对CICR的调控作用，本课题阐明了FHF2在肥厚心肌CICR调控中的作用及其机制，并为揭示心肌肥厚的发生机制提供新思路。