NRG-1-ErbB4-YAP信号轴在哺乳动物心肌再生中的作用和机制研究

The mortality of heart failure remains high at present. To find a way to induce regeneration of mature cardiomyocytes might be the key to cure heart failure. Our previous studies in the levels of genes, cells, animals and human bodies found that neuregulin (NRG) and its ErbB receptors may improve heart function by inhibiting myocardial apoptosis and promoting myocardial regeneration. Yes-associated protein (YAP) is a multi-functional transcriptional co-activator, which promotes proliferation of cells, making it an appropriate research target. Studies have shown that NRG-ErbB pathway and YAP interact and form an autocrine loop to promote cancer proliferation. Therefore, we assume that NRG-1-ErbB4-YAP pathway axis also exists in the heart and mediates myocardial regeneration. This study first analyzes the interaction between NRG-1-ErbB4 pathway and YAP in cardiomyocyte model and heart failure rat model, and explores the effect of their interaction on myocardial apoptosis, proliferation, regeneration and improvement of cardiac function. Then we further study the molecular mechanism of NRG-1-ErbB4-YAP crosstalk, and its target genes. This study will demonstrate the role of NRG-1-ErbB4-YAP axis in mediating myocardial proliferation and regeneration, paying a way for curing heart failure.

当前心衰死亡率居高不下，诱导成熟心肌细胞再生可能是未来治疗心衰的方向。我们前期在基因、细胞、动物及人体试验中均发现神经调节蛋白（NRG）及其受体ErbB通过抑制心肌凋亡、促进心肌再生而改善心功能。Yes相关蛋白(YAP)是一种多功能转录共激活因子，也介导细胞增殖。研究显示NRG-ErbB可与YAP相互作用形成自分泌环促进肿瘤增殖。我们推测心脏也存在NRG-1-ErbB4-YAP信号轴，可通过交互对话激活心肌增殖、再生。本研究在大鼠心肌细胞水平及大鼠心衰动物模型中，分析NRG-1-ErbB4与YAP在心肌细胞中是否存在交叉对话，探讨NRG-1-ErbB4-YAP信号轴对心肌凋亡、增殖、再生及改善心功能方面的影响，挖掘NRG-1-ErbB4-YAP信号轴介导心肌再生的分子机制和靶基因。本课题将阐明NRG-1-ErbB4-YAP信号轴在哺乳动物心肌增殖和再生中的作用，为心衰治疗探索初步方向。

目前心衰的治疗措施主要是抑制心肌病理性重构，但并不能从根本上解决心肌凋亡、坏死的问题，因而制约了心力衰竭的治疗效果。抑制心肌凋亡、促进心肌细胞增殖和再生可能是攻克心衰治疗的关键。本研究在探索心肌再生的信号通路NRG-1-ErbB4-YAP时，发现了CNEACR具有心肌保护作用，并进一步对其分子机制进行探索，发现了CNEACR调控的下游分子，包括HDAC7，Foxa2和RIPK3，对这些关键分子的相互作用机制及生物学意义进行了探索。研究结果显示在缺氧暴露的心肌细胞和缺血损伤的小鼠心脏中，CNEACR水平降低。CNEACR过表达抑制了缺氧暴露诱导的心肌细胞凋亡，抑制了缺血损伤诱导的小鼠心脏的心肌坏死，显著减少心肌梗死面积和改善心功能。在机制上，CNEACR直接与细胞质中的组蛋白去乙酰化酶(HDAC7)结合并干扰其核内转移，抑制HDAC7依赖的Foxa2转录降低，导致Foxa2表达增加，Foxa2可以通过与RIPK3基因的启动子区结合而抑制其转录，进而减少缺血缺氧诱导的心肌损伤和凋亡，促进心肌存活。研究结果显示干预CNEACR通路能够减少心肌细胞丢失，抑制心肌凋亡，促进心肌存活及增殖再生，有望成为缺血导致的心力衰竭的治疗靶点。