晚钠电流触发细胞凋亡致心脏传导疾病的机理研究

Cardiac arrhythmic diseases, such as sick sinus syndrome (SSS), are often associated with myocardial structural abnormalities. The underlying mechanisms for this are unclear. Mutations in SCN5A have been associated with several familial cardiac arrhythmic syndromes including SSS. We have recently showed that an increase in persistent late sodium current (INa,L) in the heart in mice with heterozygous knock-in KPQ-deletion (Scn5a+/ΔKPQ) resulted in the alterations in sinus node function and intracranial conduction. Other studies also showed the mutations in SCN5A are associated both electrical remodeling and tissue degeneration, suggesting the role of SCN5A in both cardiac electrophysiology and tissue integrity. In the present proposal, we hypothesize that enhanced INa,L induced activation of apoptotic signalling via secondary intracellular Ca2+ overload as a key mechanism for myocardial structural abnormalities and the pathogenesis of cardiac conduction diseases, we suggest that inhibition of INa,L can be a novel therapeutic approach for cardiac conduction disease associated INa,L. Using both wild type and Scn5a+/ΔKPQ mice, we will test this hypothesis by studying cellular Ca2+ homeostasis, apoptosis and associated signalling pathways, and tissue structural remodelling in the cardiac conduction system without and with treatment of Ranolazine by using a range of electrophysiological and molecular biological techniques.

心律失常如病窦综合症(SSS)等，常伴有心脏结构异常。具体机制尚未完全明确。SCN5A 基因突变和许多遗传性心律失常包括SSS有关。我们通过Scn5a+/ΔKPQ基因修饰小鼠发现晚钠电流 (INa,L)增大导致窦房结功能低下和心脏传导障碍。另有研究也证实 SCN5A 突变和心脏组织结构重构有关，这提示SCN5A 可能同时影响心电活动和组织结构。我们提出INa,L增大可能通过胞内钙超载诱导细胞凋亡，该信号传导通路是导致心肌重构和传导异常的病理生理机制；INa,L抑制剂对INa,L导致的传导异常有一定治疗作用。我们使用Scn5a+/ΔKPQ基因修饰小鼠模型，结合使用电生理和分子生物学技术来研究胞内钙稳态、凋亡相关的传导通路、心肌重构等及晚钠电流抑制剂雷诺嗪潜在的治疗价值。

心律失常如病窦综合症(SSS)等,常伴有心脏结构异常。具体机制尚未完全明 确。SCN5A 基因突变和许多遗传性心律失常包括 SSS 有关。我们通过 Scn5a+/ΔKPQ 基因修 饰小鼠发现晚钠电流 (INa,L)增大导致窦房结功能低下和心脏传导障碍。另有研究也证实 SCN5A 突变和心脏组织结构重构有关,这提示 SCN5A 可能同时影响心电活动和组织结构。我 们提出INa,L增大可能通过胞内钙超载诱导细胞凋亡,该信号传导通路是导致心肌重构和传 导异常的病理生理机制;INa,L 抑制剂对 INa,L 导致的传导异常有一定治疗作用。我们使用 Scn5a+/ΔKPQ 基因修饰小鼠模型,结合使用电生理和分子生物学技术来研究胞内钙稳态、凋 亡相关的传导通路、心肌重构等及晚钠电流抑制剂雷诺嗪潜在的治疗价值。