MicroRNA-499对心力衰竭时心房和心室肌细胞凋亡的调控作用研究

The apoptosis of cardiomyocytes plays an essential role in the development of congestive heart failure (CHF). Apoptosis of ventriculat myocytes is a causal mechanism of heart failure, and apoptosis of atrial myocytes related to CHF may create the substrate for atrial fibrillation (AF), CHF and AF form a vicious circle. However, the mechanisms of apoptosis regulation during CHF are elusive. This project group had demonstrated that miR-499 participated in inhibiting apoptosis and myocardial infarction induced by anoxia and ischemia. Cardiomyocytes apoptosis and down-regulation of miR-499 were found in CHF patients. Our preliminary experiment also revealed that atrial myocytes apoptosis was accompanied by the decrease of miR-499 level in canine model of ventricular tachypacing (VTP) induced CHF; So, we hypothesized that miR-499 could participate in inhibiting the ventricular and atrial myocytes apoptosis related to CHF, and try to test it in VTP induced canine heart failure model with upregualtion/down-regualtion of miR-499 in ventricular and atrial myocytes seperatively. At the same time, the modulating factors such as oxidative stress and p53 which in the upstream of miR-499 regulation, the potential target of miR-499 such as PDCD4 were evaluated in the the VTP induced CHF model and H2O2 injury model of ventricular and atrial myocytes. The study will shed new light on the miR-499 related signaling pathway for apoptosis resulting from CHF, and provide experiment evidence for the development of new drugs based on miR-499 in the prevention and treatment of CHF and CHF-related AF.

心肌细胞的凋亡对充血性心力衰竭（心衰）的发生和发展起重要作用。心室肌凋亡会引发和加重心衰，心衰时心房肌凋亡易引发房颤，与心衰形成恶性循环。目前对于心衰时细胞凋亡的调控机理仍不清楚。前期研究发现microRNA-499 (miR-499)能抑制缺血、缺氧时的凋亡。而心衰患者心室肌凋亡增加且miR-499显著下调，本课题组预实验显示心衰犬心房肌的miR-499显著降低且凋亡显著增加。据此，我们认为miR-499能抑制心衰时心房和心室肌凋亡。并拟利用犬心室快速起搏心衰模型，分别使心室和心房肌细胞miR-499表达上调和下调来验证。同时，利用犬的起搏心衰模型以及心室和心房肌细胞的H2O2损伤模型，对miR-499调控的上游环节如氧化应激和p53、下游靶点如PDCD4进行分析。通过研究可明确心衰时miR-499调控细胞凋亡的信号通路，并为利用miR-499开发防治心衰以及心衰合并房颤的药物提供依据。

心肌细胞的凋亡对充血性心力衰竭（心衰）的发生和发展起重要作用。心室肌凋亡会引发和加重心衰，心衰时心房肌凋亡易引发房颤，与心衰形成恶性循环。目前对于心衰时细胞凋亡的调控机理仍不清楚。前期研究发现microRNA-499 (miR-499)能抑制缺血、缺氧时的凋亡。而心衰患者心室肌凋亡增加且miR-499显著下调，本课题组预实验显示心衰犬心房肌的miR-499显著降低且凋亡显著增加。据此，我们认为miR-499能抑制心衰时心房和心室肌凋亡。并拟利用犬心室快速起搏心衰模型，分别使心室和心房肌细胞miR-499表达上调和下调来验证。同时，利用犬的起搏心衰模型，对miR-499调控的上游环节如氧化应激和p53、下游靶点如PDCD4进行分析。通过研究可明确心衰时miR-499调控细胞凋亡的信号通路，并为利用miR-499开发防治心衰以及心衰合并房颤的药物提供依据。