激活素A/卵泡抑素系统失衡在心衰心肌细胞凋亡中的作用及机制

It had confirmed that activin A played an important role in promoting the liver and the kidney fibrosis. The current study found that activin A expressed continuously high in the serum of heart failure patients and in the myocardium of heart failure rats while its exocellular antagonist-follistatin reduced or had no change. The increase of activin A/follistatin ratio participated in myocardial fibrosis and cardiomyocyte apoptosis, the conclusion in the chronic injury research is however different and controversial. We assume that the activin A and follistatin as a system played a part in cardiomyocyte apoptosis, of which the expression time and level were two directional. Thus, balancing the system would improve cell apoptosis. As a result, we will study the significance of expression imbalance of activin A/follistatin system and its mechanism in different periods of heart failure, in different concentrations, in the existence of activin A exocellular antagonist and activin receptor antagonist. In the animal experiment level and cell culture level, we consider the system effect on cardiomyocyte apoptosis through making follistatin over-expressed for balancing this system. After that, we will block the signaling pathway before, on and after the activin receptor in the animal level and the cell level, and detect the expressions of upstream and downstream molecules on blocking sites and apoptosis levels. Our goal is clarifying the ActRIIA-Smads signaling pathway and its mechanism where activin A participates in cardiomyocyte apoptosis. As a result, we will provide new targets on improving ventricular remodeling and treating heart failure.

激活素A在肝脏、肾脏纤维化中的促进作用已证实。目前研究发现在心衰患者血清及心衰大鼠心肌中激活素A持续高表达,其胞外拮抗剂卵泡抑素降低或无改变,激活素 A/卵泡抑素比值升高参与了心肌纤维化和心肌细胞凋亡,但在慢性损伤的研究中结论不同并存有争议。我们假设激活素A和卵泡抑素作为一个系统参与心肌细胞凋亡,并有时间和表达水平的双向性,那么纠正系统的失衡就可以改善细胞凋亡。因此我们将在动物实验整体水平和细胞培养层面研究激活素A/ 卵泡抑素系统在心衰不同时期、不同浓度、存在激活素A胞外拮抗剂及受体拮抗剂的情况下表达失衡的意义及机制,并通过卵泡抑素过表达改善这个系统的失衡,探讨其对心肌细胞凋亡的影响；并在动物整体水平和细胞水平分别阻断激活素A受体前、受体和受体后途径,检测阻断上游及下游分子的表达及细胞凋亡水平,明确其ActRIIA-Smads信号传导途径及机制,为改善心室重塑、治疗心衰提供新靶点。

激活素A(activin A，ACT-A)属于TGF-β超家族成员，卵泡抑素（FS）是ACT-A的细胞外天然结合蛋白，拮抗ACT-A的生物学作用。ACT-A/FS系统失衡与心衰的发生、发展过程有关，然而其对心衰的作用及机制均不明确。本研究通过构建心梗后心衰大鼠模型及体外心肌细胞模型，深入探讨了心衰不同时期心肌细胞凋亡及Activin A/ FS系统失衡情况，并探讨了Activin A/ FS系统失衡对心衰心肌细胞凋亡的影响及机制。研究明确了心衰不同时期Activin A、FS表达水平，阐明了心衰不同时期Activin A/ FS系统失衡的情况；明确了不同浓度Activin A对心衰心肌细胞凋亡的影响； 明确了不同浓度Activin A对心衰心肌内质网应激的影响；阐明了Activin A影响心肌细胞凋亡的信号转导途径。以上问题的阐明，对阐明心衰机制、寻找治疗心衰的新靶点具有重要意义。.本课题取得成果如下：项目资助已发表SCI论文10篇（尚有2篇待发表），核心论文3篇；本课题已培养博士研究生5名（其中1名为八年制，已取得博士学位），硕士研究生4名，尚有5名博士研究生预计2017年6月答辩。课题负责人以本课题的研究成果作为心衰网络调控机制的一部分，于2016年度申报并获得吉林省科学技术进步奖一等奖。此外，在本课题成果的支持下，课题负责人于2016年度获得国家发改委资助500万元，建立吉林省心血管重大疾病精准医学分子生物学实验中心，单位配套经费：2500万元。