Abstract：
The reactivated adult epicardium produces epicardium-derived cells (EPDCs) via epithelial-mesenchymal transition (EMT) to benefit the recovery of the heart after myocardial infarction (MI). SMARCA4 is the core catalytic subunit of the chromatin re-modeling complex, which has the potential to target some reactivated epicardial genes in MI. However, the effects of epicardial SMARCA4 on MI remain uncertain. This study found that SMARCA4 was activated over time in epicardial cells following MI, and some of activated cells belonged to downstream differentiation types of EPDCs. This study used tamoxifen to induce lineage tracing and SMARCA4 deletion from epicardial cells in Wt1-CreER;Smarca4fl/fl;Rosa26-RFP adult mice. Epicardial SMARCA4 deletion reduces the number of epicardial cells in adult mice, which was related to changes in the activation, proliferation, and apoptosis of epicardial cells. Epicardial SMARCA4 deletion reduced collagen deposition and angiogenesis in the infarcted area, exacerbated cardiac injury in MI. The exacerbation of cardiac injury was related to the inhibition of generation and differentiation of EPDCs. The alterations in EPDCs were associated with inhibited transition between E-CAD and N-CAD during the epicardial EMT, coupled with the down-regulation of WT1, SNAIL1, and PDGF signaling. In conclusion, this study suggests that Epicardial SMARCA4 plays a critical role in cardiac injury caused by MI, and its regulatory mechanism is related to epicardial EMT. Epicardial SMARCA4 holds potential as a novel molecular target for treating MI.
摘要：
重新激活的成人心外膜通过上皮-间质转化（EMT）产生心外膜衍生细胞（EPDC），以促进心肌梗死（MI）后心脏的恢复。SMARCA4是染色质重塑复合物的核心催化亚基，它有可能靶向心肌梗死中一些重新激活的心外膜基因。然而,心外膜SMARCA4对MI的影响尚不确定.这项研究发现，随着时间的推移，MI后的心外膜细胞中的SMARCA4被激活，部分活化细胞属于EPDCs的下游分化类型。这项研究使用他莫昔芬从Wt1-CreER的心外膜细胞中诱导谱系追踪和SMARCA4缺失;Smarca4fl/fl;Rosa26-RFP成年小鼠。心外膜SMARCA4缺失减少成年小鼠的心外膜细胞数量，这与激活的变化有关，扩散,和心外膜细胞凋亡。心外膜SMARCA4缺失减少了梗死区的胶原沉积和血管生成,MI加重心脏损伤。心脏损伤的加重与抑制EPDCs的产生和分化有关。在心外膜EMT期间，EPDCs的改变与E-CAD和N-CAD之间的转换抑制有关，与WT1、SNAIL1和PDGF信号的下调有关。总之,这项研究表明，心外膜SMARCA4在心肌梗死引起的心脏损伤中起关键作用，其调控机制与心外膜EMT有关。心外膜SMARCA4具有作为治疗MI的新型分子靶标的潜力。
