类泛素蛋白FAT10稳定致缺血性室性心律失常离子通道蛋白的机制与干预研究

The lethal ischemic ventricular arrhythmias are the major cause of sudden cardiac death in patients with coronary heart disease. It has been known that the alternation of the expression and function in several cardiac ionic channels (i.e. Nav1.5 and Kv7.1) is associated with lethal ischemic ventricular arrhythmias while the pathogenic mechanism is unclear, and no effective medicine is available. Our previous study firslty explored that ubiquitin-like protein FAT10 could improve the protein stabilization in heart . Besides, we also demonstrated that the expression level of FAT10, Nav1.5 and Kv7.1 were increased in hypoxic cardiomyocytes. Accordingly, we speculate that the up-regulation of Nav1.5 and Kv7.1 by FAT10 might be involved in ischemia-induced ventricular arrhythmias. Expressional and functional studies will be evaulated in myocytes from the FAT10 knock-out mice, transgenic mice, and null mice by multiple experimental techniques to confirm the role of FAT10, Nav1.5 and Kv7.1 in the ischemic ventricular arrhythmias, to explore the stabilization mechanism of Nav1.5 and Kv7.1 by FAT10 and study the effective treatment of FAT10 inhibiting with traditional anti-arrhythmic drugs. Finally, the detailed mechanisms of ventricular arrhythmias mediated by FAT10 would be clarified and the potential anti-ischemia arrhythmic drug target could be found.

缺血性室性心律失常是导致冠心病患者猝死的主要因素。已知多种离子通道表达和功能异常（包括钠通道Nav1.5和钾通道Kv7.1）参与了缺血性室性心律失常发生，但其具体机制仍不清楚。前期我们报道类泛素蛋白FAT10具有促进蛋白稳定性的作用，缺氧可以同时增加心肌细胞FAT10、Nav1.5 和Kv7.1表达。由此我们推测FAT10可能通过上调Nav1.5和Kv7.1介导缺血性室性心律失常。为了验证这一假设，本课题将应用FAT10基因敲除和转基因小鼠等多种实验手段，确认FAT10 在缺血性室性心律失常中作用；解析FAT10稳定Nav1.5和Kv7.1蛋白表达的分子机制，探索阻滞FAT10并联合传统抗心律失常药物的有效治疗作用。最终我们将阐明FAT10介导室性心律失常的详细机制，并有可能找到治疗缺血性室性心律失常多通道阻滞作用的潜在药物靶点。

缺血性室性心律失常是导致冠心病患者猝死的主要因素。已知多种离子通道表达和功能异常（包括钠通道Nav1.5和钾通道Kv7.1）参与了缺血性室性心律失常发生，但其具体机制仍不清楚。本课题拟应用FAT10基因敲除和转基因小鼠等多种实验手段，确认FAT10 在缺血性室性心律失常中作用；解析FAT10稳定Nav1.5和Kv7.1蛋白表达的分子机制，探索阻滞FAT10并联合传统抗心律失常药物的有效治疗作用。课题按照计划进行，取得较好的研究成果：（1）在缺血性室性心律失常中，FAT10心脏特异性敲除小鼠动作电位时程增加，动作电位幅度降低；（2020年Cell death and disease录用，IF：6.304）（2）FAT10增加钠离子通道密度，影响晚钠电流；（2020年Cell death and disease录用，IF：6.304）（3）FAT10通过Nedd-4与泛素竞争钠离子通道Nav1.5的结合，进而影响Nav1.5的泛素化降解，稳定Nav1.5的蛋白表达；（2020年Cell death and disease录用，IF：6.304）（4）FAT10增强钾离子通道IKs电流；（论文撰写中）（5）FAT10通过直接与Kv7.1结合，抑制Kv7.1蛋白的泛素化降解，稳定Kv7.1的表达；（论文撰写中）（6）在心肌缺血中，FAT10通过稳定小窝蛋白Caveolin-3表达抑制心肌细胞凋亡，发挥心肌保护作用；（2018年Journal of Molecular and Cellular Cardiology录用，IF：5.055）（7）在心肌缺血中，FAT10通过与SUMO-1竞争SIRT1结合位点，抑制自噬体膜延伸，从而抑制自噬，发挥心肌保护作用；（2020年Journal of Molecular and Cellular Cardiology录用，IF：4.133）（8）锚蛋白-B新突变（ANK-B p.Q1283H）降低局部磷酸酶活性导致兰尼定受体（RYR2）磷酸化水平异常增加，进而导致心律失常的发生；（2018年Circulation录用，IF：23.044）（9）糖尿病大鼠心脏心律失常易感性增加，O-GlcNAc糖基化修饰钠离子通道Nav1.5蛋白，Nav1.5峰电流减少，参与糖尿病心肌损伤所致心律失常；(2018年IJC录用，IF：3.471）

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