雄激素通过介导HCN4的表达参与心率调节的机制研究

As one of the most common arrhythmias, bradycardia has a high mortality and disability rate. However, its pathogenesis hasn't been fully illustrated. HCN4 is considered to be the pacemaker ion channel maintaining basic heart rate and acts as the final common path for other factors regulating heart rate. Abnormality of the function and expression of HCN4 is a crucial physiopathologic mechanism in bradycardia. Androgen has been found to be related to change of heart rate and regulation of HCN4 expression in previous studies, but the precise influence and concrete mechanism weren't explicit. On such basis, we hypothesized that the influence of androgen on heart rate regulation is mediated by modulating HCN4 expression. Our study will be divided into two parts. The first part is designed to investigate the influence of different doses of testosterone on the function and expression of HCN4 as well as the definite mechanism at gene and molecular levels using neonatal rat myocardial cells transfected with human HCN4 genes. Furthermore, the verification of our hypothesis will be carried out by canine models in the second part. The mechanism that the influence of androgen on heart rate regulation is mediated by modulating HCN4 expression will be investigated in this study for the first time. By illuminating how androgen affects the electrophysiological characters of cardiac pacemaker cells, we will provide a new insight into the pathogenesis basis of bradycardia and a new idea for its treatment.

缓慢性心律失常是临床常见的致死致残疾病之一，发病机制尚不明确。HCN4是目前公认维持基本心率的主要离子通道，其功能与表达异常是缓慢性心律失常的重要病理生理机制，也是各因素参与心率调节的最终通路。研究发现，雄激素与心率变化有关，并在一定程度上调控HCN4基因的表达，但作用与具体机制均未明确。结合国内外文献，我们提出"雄激素通过介导HCN4的表达，参与基本心率的维持与调节"的假设。本研究拟通过在转染人HCN4的乳鼠心肌细胞上探讨不同剂量睾酮对HCN4功能与表达的影响，并从基因分子水平阐明雄激素参与心率调节的具体机制。进一步在犬模型上验证睾酮通过上调HCN4基因进而维持与调节心率的作用。本课题将首次探讨雄激素通过介导HCN4的表达影响心率的机制，揭示雄激素对心肌起搏细胞电生理特性的影响，从新的角度阐明缓慢性心律失常的发病基础，为今后心动过缓的防治提供新思路，具有重要的理论意义和一定的应用价值。

缓慢性心律失常是临床常见的致死致残疾病之一，发病机制尚不明确。HCN4 是目前公认维持基本心率的主要离子通道，其功能与表达异常是缓慢性心律失常的重要病理生理机制，也是各因素参与心率调节的最终通路。研究发现，雄激素与心率变化有关，并在一定程度上调控HCN4基因的表达，但作用与具体机制均未明确。结合国内外文献，我们提出“雄激素通过介导HCN4 的表达，参与基本心率的维持与调节”的假设。我们探究了雄激素对HCN4表达的影响。之后通过研究影响乳鼠心肌细胞自律性的因素的过程中，我们在基因分子水平发现，ISL-1基因表达增加促进心室肌细胞向起搏样细胞转化，并在动物模型上进行了验证。本课题探讨雄激素能否通过介导 HCN4 的表达影响心率，揭示ISL-1基因对心肌起搏细胞电生理特性的影响，从新的角度阐明缓慢性心律失常的发病基础，为今后心动过缓的防治提供新思路，具有重要的理论意义和一定的应用价值。