活化成纤维细胞致梗死后室性心律失常新机制研究

项目名称： 活化成纤维细胞致梗死后室性心律失常新机制研究

项目编号： No.81200142

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 王德国

作者单位： 皖南医学院

项目金额： 23万元

中文摘要： 室性心律失常（VAs）是心肌梗死患者猝死的主要原因，其中心脏成纤维细胞（CFs）的电生理调控作用是研究的盲区。新近的计算机仿真及细胞共培养结果提示CFs及其活化的MFs可与心肌细胞（CMCs）形成异源性缝隙连接（GJ），可能参与VAs的发生机制。但心脏中是否存在这种异源性GJ及MFs是否与GJ重构有关等问题尚未阐明。本项目在我们前期研究发现MFs分泌的基质金属蛋白酶（MMPs）与Cx43重分布有关的基础上，推测MFs调控心脏GJ偶联是VAs发生的新机制。为此，本项目拟以在体、心肌组织片及细胞共培养模型，利用心脏电生理及多导微电极阵列仪（MEA）观察MFs对GJ介导的心电快速传导的影响，着重探讨CFs活化/MMPs激活/N-cadherin裂解在Cx43重分布中的作用及其电生理影响，从新的视角阐明MFs参与梗死后VAs的发生机制，为VAs治疗指出新的方向。

中文关键词： 成纤维细胞；室性心律失常；心肌梗死；缝隙连接；

英文摘要： Ventricular arrhythmias （VAs）are the main cause of sudden death in patients with myocardial infarction （MI）.Previous studies were focused on electrical remodelling of cardiac myocytes and neglected the role of cardiac fibroblasts （CFs） in electrophysiological regulation. Recent studies from computer simulation and coculture model suggested that heterocellular gap junction（GJ）coupling between cardiac myocytes (CMCs) and myofibroblasts(MFs) alters electrophysiological properties in vitro.However，it was unclear whether exist the heterocellular GJ in adult heart and the relationships between MFs and GJ remodelling in the infarcted heart. Our privious study showed that infusion of condition medium from MFs culture reduce GJ coupling between cardiac myocytes in isolated rats hearts and lead to increased susceptibility to VAs. The effects might be associated with matrix metalloproteinases (MMPs)for Doxycycline (a none-specific MMPs inhibitors) could preserve GJ couple from disruption of MFs condition medium. Therefor,we propose a new hypothesis that MFs have ventricular proarrhythmogenisis through regulation GJ coupling. In this project, we will systematically investigate ventricular proarrhythmogenic mechanisms of MFs using several electrophysiological techiques such as electrocardiogram (ECG),monophasic action pote

英文关键词： cardiac fibroblasts；Ventricular arrhythmias；myocardial infarction；gap junction；