心房电重构在房颤促进房颤发生与持续过程中发挥重要作用。本课题组前期研究发现房颤时钙依赖的中性蛋白酶calpain激活，可降解锚蛋白ankyrin-G。最近文献报道ankyrin-G可与心肌细胞膜钠离子通道Nav1.5相结合而调节钠内流；Nav1.5基因突变可引起心房颤动等遗传性心律失常。故提出假设：房颤心房电重构存在正反馈环路- - 房颤时calpain激活并降解ankyrin-G，影响ankyrin-G与Nav1.5结合，Nav1.5表达减少和运输障碍，跨膜钠电流失衡，导致心房电重构，使房颤持续。但ankyrin-G-Nav1.5通路在心房电重构中的作用与机制尚不明确。本课题拟构建心房快速起搏犬和HL-1心房细胞系模型，应用calpain抑制剂和转染calpastatin进行干预，来验证上述假设。本研究将为心房颤动心房电重构的药理学干预提供新的靶点与方向。

Atrial ?brillation (AF) by itself induces electrical remodeling favoring its recurrence and persistence. However, the precise mechanism of electrical remodeling in AF is unknown. Previous studies have shown that AF is accompanied by intracellular calcium overload, which causes activation of the calcium-dependent neutral proteases-calpain. Cytoskeletal protein ankyrin-G can be degraded by calpain. Ankyrin-G is required critically for voltage-gated sodium channels (Nav) targeting to cardiac emembrane domains. Ankyrin-G dysfunction has been linked with abnormal ion channel membrane organization. Nav1.5 is the primary voltage-gated sodium channel in heart and generates the rapid upstroke of the cardiomyocyte action potential. Human Nav1.5 gene (SCN5A) loss-of-function mutations may lead to many cardiac phenotypes, including Brugada syndrome, sick sinus syndrome and atrial ?brillation. The overall hypothesis is that calpain-ankyrin-G-Nav1.5 pathway is involved in electrical remodeling in atrial ?brillation: calpain can degrade ankyrin-G and disturb localization and expression of Nav1.5, resulting in inbalance of ions and atrial ?brillation. The objective of this proposal is to elucidate the role of and mechanisms underlying calpain-ankyrin-G-Nav1.5 pathway in electrical remodeling during atrial ?brillation. We will use a canine model of atrial ?brillation produced by prolonged atrial pacing and rapidly stimulated HL-1 atrial myocytes to observe the possibility of preventing electrical remodeling by regulating calpain-ankyrin-G-Nav1.5 pathway. This is a highly innovative proposal that focuses on a novel concept. The outcomes will enhance the understanding of the pivotal mechanisms of electrical remodeling in atrial ?brillation and lead to new therapeutic targets for this important problem.