miR-199a-5p调控CAV1影响心肌细胞钠通道参与房颤发生的机制研究

Atrial fibrillation and related complications seriously affect the life quality of middle-aged and elderly people, and there is a lack of safe and effective treatment and prevention methods. Genome-wide association study and our earlier research revealed CAV1 was a susceptibility gene to AF and reflected a decreased mRNA level with risk allele. After resequencing the CAV1 3 'UTR region, a heterozygous mutation site located in known targeted binding region of miR-199a-5p was found. CAV1 interacts with many ion channels or affects current, so far it is only found co-located with sodium channel protein, we speculated that the regulation of CAV1 expression by miR-199a-5p may affect the transport of sodium channel protein and abnormal membrane localization, and change the membrane potential of myocardium, which may be involved in the pathogenesis and development of AF. In this study, we firstly identify miR-199a-5p could target CAV1 in cardiomyocytes, secondly we will study whether regulation of CAV1 affect sodium currents in cardiac myocytes and sodium channel protein trafficking, thirdly, we will construct miR-199a-5p overexpressing mice to identify the regulation of CAV1 by miR-199a-5p in AF and biological mechanism in vitro.

房颤（AF）及相关并发症严重影响中老年人生活质量，且目前缺乏安全有效的治疗预防途径，全基因组关联分析及我们前期研究显示CAV1为AF易感基因之一，该基因增加AF风险与自身转录水平降低密切相关；重新测序CAV1 3’UTR区后发现一例杂合变异位点，位于miR-199a-5p已知靶向结合区域。CAV1与众多离子通道存在相互作用或影响电流，而与钠通道蛋白仅发现共定位，申请人推测miR-199a-5p调控CAV1表达极可能影响钠通道蛋白转运和膜定位异常并改变心肌细胞膜电位，参与AF的发生发展。本研究将1）明确心肌细胞中miR-199a-5p对CAV1表达调控，2）发现CAV1下调对心肌细胞钠电流、钠通道蛋白转运及膜定位的影响，明确miR-199a-5p通过负调控CAV1增加房颤发病风险；3）动物模型在体水平明确miR-199a-5p调控CAV1对AF的影响，为临床AF的防治提供新的理论基础。

房颤（AF）及相关并发症严重影响中老年人生活质量，且目前缺乏安全有效的治疗预防途径，全基因组关联分析及我们前期研究显示CAV1为AF易感基因之一，该基因增加AF风险与自身转录水平降低密切相关，申请者前期发现在心肌细胞中miR-199a-5p对CAV1存在表达调控作用，目前CAV1已知与众多离子通道存在相互作用或影响电流，而与钠通道蛋白仅发现共定位，申请人推测miR-199a-5p调控CAV1表达极可能影响钠通道蛋白转运和膜定位异常并改变心肌细胞膜电位，参与AF的发生发展。本项目研究了心肌细胞中miR-199a-5P对CAV1表达调控作用，通过检测CAV1-/-小鼠相关表型，发现CAV1-/-小鼠存在心电异常，且其心肌细胞动作电位发生明显改变，我们同时对CAV1参与房颤的发生机制进行了初步探索，发现CAV1可促进心肌纤维化及心肌细胞重构。除了研究miR-199a-5P及CAV1在房颤发生发展中的作用，我们也研究了其他MiRNA参与房颤发生的调控作用，发现miR-190a-5p通过抑制内源性IL-2表达，引起SCN3B钠离子通道电流增加，而抑制miR-190a-5p的表达，钠电流减低效应明显，初步探索了miR-190a-5p对IL-2、SCN3B调控作用，以及miR-190a-5p/IL-2/SCN3B途径在心律失常发生中的作用。