SK4通道在浦肯野纤维致心律失常性电活动中的作用及机制研究

批准号:
82000310
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
侯建文
依托单位:
学科分类:
心电活动异常与心律失常
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
侯建文
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中文摘要
心血管疾病是威胁人类健康的主要原因之一,而室性心律失常是导致心源性猝死的首要原因。研究表明心脏浦肯野纤维在室性心律失常的触发和维持中起着重要作用,但其机制仍有待进一步阐明。我们的前期研究发现,与心室肌相比,小电导钙激活钾通道4(SK4)在浦肯野纤维中高表达,病理状况下细胞内钙浓度升高使其激活更加显著,而抑制SK4通道能够有效终止浦肯野细胞电紊乱及相关心律失常,提示SK4通道激活可能与浦肯野纤维心律失常易感性密切相关。但是病理情况下SK4通道激活如何调控浦肯野纤维电活动及其致心律失常的分子机制并不清楚。综上我们提出科学假说:浦肯野纤维高表达SK4通道,病理状态下其胞内钙浓度增高使得SK4通道过度激活进一步加重细胞内钙紊乱导致复极离散度增加、自律性异常并触发心律失常。本项目旨在揭示SK4通道对心脏浦肯野纤维电生理功能的调控作用并阐明其致心律失常机制,为临床治疗浦肯野纤维起源心律失常提供新方向。
英文摘要
Cardiovascular diseases remain to be one of the major causes that threaten human health, among which ventricular arrhythmias are the leading causes of sudden cardiac death. Previous studies indicate cardiac Purkinje fibers which are more susceptible to develop arrhythmias play an important role in triggering and maintaining ventricular arrhythmias, however the underlying mechanisms remain to be fully explored. Our previous study shows that the expression level of the small-conductance calcium-activated potassium channel type 4 (SK4) was higher in Purkinje fibers compared with that in ventricular muscle, corresponding to more SK4 channel activation under pathological condition when intracellular calcium concentration increased, and pharmacological inhibition of SK4 channel effectively eliminate Purkinje-related arrhythmias, which indicates abnormal SK4 channel activation may contribute to the arrhythmia susceptibility of Purkinje fibers. However, the molecular mechanisms of SK4 channel in modulating electrical activity and in promoting arrhythmias in Purkinje fibers are still unclear. Above all, we hypothesis that abundant distribution of SK4 channel in Purkinje fibers contribute to its excessive activation under pathological condition with the elevation of intracellular calcium, which in turn further aggravate intracellular calcium disorder, increase repolarization dispersion and automaticity, and finally trigger arrhythmias. This project is aimed to explore the role of SK4 channel in cardiac Purkinje fibers and further reveal its potential arrhythmogenic mechanism. Our study will provide novel insight in treating arrhythmias originated from Purkinje fibers in clinical practice and pharmacological inhibition of SK4 channel may be an alternative choice of arrhythmia control.
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专利列表
瞬时受体电位M4通道在浦肯野纤维中的作用及致心律失常机制研究
- 批准号:LQ21H020008
- 项目类别:省市级项目
- 资助金额:0.0万元
- 批准年份:2020
- 负责人:侯建文
- 依托单位:
国内基金
海外基金
