LncRNA FAF通过FGF9/FGFR信号通路抑制急性心肌梗死后心肌细胞焦亡的作用机制研究

FAF is a novel lncRNA , which has been identified to be aberrantly expressed in the myocardial tissue of acute myocardial infarction (AMI) rats using sequence analysis in our pilot study. The latest data suggest that cell pyroptosis is one of the major causes of cardiomyocyte loss after AMI. Our preliminary study has identified that a significant decrease of the expression of FAF, in both AMI rats and hypoxic-ischemic cardiomyocyte model, as a positive regulator of Fibroblast growth factor 9 (FGF9). Our further study also found that FGF9 could significantly inhibit activation of caspase-1 and -3 in hypoxic-ischemic cardiomyocyte. These findings indicate that FAF may play a protective role in cardiomyocyte pyroptosis after AMI. To our knowledge, it is not yet clear whether lncRNA is involved in the regulation of cell pyroptosis after AMI. Accordingly, we hypothesized that in the process of myocardial ischemia and hypoxia, dowm-regulated FAF could suppress the expression of FGF9, and subsequently induce cardiomyocyte pyroptosis. The aim of this study is to investigate the mechanism by which FAF inhibits myocardial cell pyroptosis by regulating FGG9/FGFR signaling pathway in molecular, cardiomyocyte and animal models. Our study might reveal a novel mechanism involving FAF in regulating cardiomyocyte pyroptosis after AMI and provide a new therapeutic avenue for AMI.

LncRNA FAF是本课题组前期在急性心肌梗死（AMI）大鼠心肌组织中测序筛选出异常表达的新基因。最新资料提示细胞焦亡是AMI后心肌细胞丢失的主要原因之一。我们的预实验发现AMI大鼠和乳鼠原代心肌细胞缺血缺氧模型中，FAF表达均显著降低，并且正向调控成纤维细胞生长因子9（FGF9）表达。进一步研究发现FGF9可以抑制心肌细胞焦亡相关蛋白水解酶caspase-1/3活化，提示FAF可能在AMI后心肌细胞焦亡中起保护作用。目前尚无心肌细胞焦亡相关lncRNA功能研究的报道。据此提出科学假说：心肌细胞缺血缺氧，FAF表达下降，通过下调FGF9表达，从而促进AMI后心肌细胞焦亡。本项目将从分子、细胞和动物三个层次探讨FAF通过FGF9/FGFR信号通路抑制AMI后心肌细胞焦亡的作用机制。本研究将从LncRNA FAF这个新视点揭示AMI后心肌细胞焦亡的机制，为AMI的治疗提供新的思路和靶点。

LncRNA FAF是本课题组前期在急性心肌梗死（AMI）大鼠心肌组织中测序筛选出异常表达的新基因。最新资料提示细胞焦亡是AMI后心肌细胞丢失的主要原因之一。我们的预实验发现AMI大鼠和乳鼠原代心肌细胞缺血缺氧模型中，FAF表达均显著降低，并且正向调控丝氨酸/苏氨酸蛋白激酶2（PAK2）。进一步研究发现LncRNA FAF可通过调控miR-185-5p与丝氨酸/苏氨酸蛋白激酶2（PAK2）轴调控焦亡相关蛋白水解酶caspase-1活化，为急性心肌梗死的治疗提供新的思路与潜在作用靶点。目前尚无PAK2蛋白及相关lncRNA功能在心肌细胞焦亡中研究的报道。据此提出科学假说：心肌细胞缺血缺氧，FAF表达下降，上调miR-185-5p表达同时过内源性竞争结合机制下调了PAK2的表达，从而促进AMI后心肌细胞焦亡。本项目将从分子、细胞和动物三个层次探讨FAF通过miR-185-5p/PAK2信号通路抑制AMI后心肌细胞焦亡的作用机制。本研究将从LncRNA FAF这个新视点揭示AMI后心肌细胞焦亡的机制，为AMI的治疗提供新的思路和靶点。