心脏成纤维细胞EphrinB2介导心肌细胞EphB4受体在心肌梗死后心室重塑中的作用及机制

内皮细胞间EphrinB2-EphB4是血管新生经典通路，但我们前期发现心脏EphrinB2主要在成纤维细胞表达，对心肌梗死后心肌纤维化具促进作用。最近我们研究发现，小鼠心脏EphrinB2敲低导致心肌梗死面积、心肌坏死性凋亡增加；但成年心肌细胞并不表达EphrinB2，主要表达EphB4受体，缺氧心肌细胞不表达EphrinB2，但显著上调EphB4。EphrinB2活性肽可抑制心肌细胞坏死性凋亡分子RIP3表达，而心肌细胞EphB4敲低则阻断了EphrinB2的作用。这些结果提示心脏成纤维细胞EphrinB2通过EphB4受体调控心肌细胞坏死性凋亡。本研究拟在前期结果基础上，利用成纤维细胞EphrinB2、心肌细胞EphB4条件性敲除小鼠心肌梗死模型，深入研究EphrinB2-EphB4在心肌梗死后心室重塑中的作用及机制，并评估EphrinB2不同时机和方式干预对心梗后心室重塑的影响。

Endothelial EphrinB2-EphB4 signaling is a classical angiogenic pathway. Our previous study first discovered that cardiac EphrinB2 was mainly expressed in fibroblasts, and fibroblast-derived EphrinB2 played a pro-fibrotic role after myocardial infarction (MI). Our recent experiments found that cardiac EphrinB2 knockdown led to the enlargement of infracted area, increase of myocardium necroptosis after MI in mice. However，EphrinB2 was rarely expressed in adult cardiomyocytes which highly expressed EphB4. EphrinB2 remained barely detectable in cardiomyocytes, while EphB4 was significantly up-regulated under hypoxia. Soluble EphrinB2 peptide inhibited necroptosis regulator RIP3 expression in cultured cardiomyocytes, while EphB4 knockdown in cardiomyocytes blocked the protective effect of EphrinB2 on cardiomyocyte necroptosis. These results strongly indicated that cardiac fibroblast-derived EphrinB2 mediating cardiomyocyte necroptosis through cardiomyocyte-derived EphB4 receptor in MI model. Based on our previous data, this project will focus on exploring the role and mechanism of EphrinB2-EphB4 signaling in cardiac remodeling after MI by using fibroblast-EphrinB2 and cardiomyocyte-EphB4 conditional knockout mice model of myocardial infarction. Finally, the effects of the different intervention of EphrinB2 at different time points on cardiac remodeling after MI will also be evaluated.