desmin变化在心衰时机械电反馈中的作用研究

The malignant arrhythmias, as one of main reasons of sudden cardiac death, affect the prognosis of heart failure (HF). However, the mechanisms are unclear. Mechanoelectric feedback (MEF) has been verified to be relevant to the malignant arrhythmias in recent years. Desmin is one of intermediate filaments of cytoskeletons and could be involved in MEF as mechanoelectric transducers. So the changes of desmin in HF might be related with the malignant arrhythmias. We have found that there was high incidence rate of ventricular arrhythmias in HF rats with ventricular asynchrony and the decrease of desmin and SERCA2a was more obvious. We inferred that MEF might affect Ca2+ recycle via desmin, which led to arrhythmias. In this study, using rat HF model and desmin siRNA model with rescue study, we will discuss the influence of MEF on the decrease of desmin in the end stage of HF from the point of stretch-activated ion channels. We will also study the mechanisms of arrhythmias caused by the decease of desmin through the its influence on the expression of NF-κB pathway and its downstream molecule. This project would provide a possible new and intriguing target for the prevention and treatment of the malignant arrhythmias in HF.

恶性心律失常作为猝死的主要原因之一，严重影响心衰患者的预后，但对其机制一直未能阐明。机械电反馈近来被证实与恶性心律失常的发生相关，结蛋白（desmin）属细胞骨架的中间丝蛋白，作为机电转导器可参与到机械电反馈过程中，提示心衰时desmin的变化可能与恶性心律失常的发生有关。我们前期工作发现心室存在非同步运动的心衰大鼠室性心律失常发生增加，同时desmin和SERCA2a的蛋白减少更为明显，推测机械电反馈通过desmin途径影响钙循环导致心律失常的发生。本项目中，我们应用心衰大鼠和desmin siRNA模型及rescue实验，从牵张激活离子通道的角度探讨机械牵张在心衰终末期desmin减少中的作用，并从desmin减少影响NF-κB通路及其下游分子蛋白mRNA表达的角度，探讨desmin减少致心律失常发生的机制。本研究为探寻防治心衰时恶性心律失常的干预靶点提供依据。

机械电反馈与心衰时恶性心律失常的发生关系密切，结蛋白（desmin）作为机电转导器可参与到机械电反馈过程中，提示心衰时desmin的变化可能与恶性心律失常的发生有关。我们通过分子生物学，免疫学，siRNA，电镜等技术手段，以大鼠心衰模型、乳鼠心肌细胞为研究对象，从整体、细胞及分子水平探讨：①心衰时desmin的变化；②探讨心衰时desmin表达减少的机制，明确机械牵张在desmin表达减少中的作用；③揭示心衰时desmin表达减少致心律失常发生的机制。旨在明确desmin在心衰时的变化对恶性心律失常发生的影响。为探寻防治心衰时恶性心律失常的干预靶点提供依据。研究表明，机械牵张可通过desmin途径介导NF-κB激活使肌浆网SERCA2a表达改变继而影响Ca2+循环导致心律失常。