Lin28a/Mst1信号通路逆转心肌梗死后左室重构的机制研究

Autophagy and apoptosis are important mechanisms of left ventricular remodeling after myocardial infarction (MI). The precise regulation of autophagy and apoptosis determine the degree cardiomyocyte damage and cardiac function. However, the regulation mechanism and the interaction between autophagy and apoptosis after MI were not well understood. Our preliminary study suggested that Mammalian Sterile20-like Kinase1 (Mst1) inhibited autophagy, promoted apoptosis and participated in the left ventricular remodeling after MI. Lin28a inhibited Mst1 phosphorylation and improved left ventricular function after MI, which may reduce myocardial injury after MI by inhibiting Mst1. Whether Lin28a/Mst1 signaling pathway is able to reverse the progression of left ventricular remodeling after MI still needs further investigation. Lin28a, Mst1 transgenic mice and knockout mice will be used to construct animal models of MI in the present project. The roles of Lin28a/ Mst1 signaling in the progression of left ventricular remodeling after MI and the interaction between autophagy and apoptosis will be investigated. The present project may help develop the new treatment strategy to reduce the high mortality of MI.

自噬和凋亡是心肌梗死后左室重构的重要机制，其精细调控决定了心肌细胞的损伤程度和心脏功能。然而，心肌梗死后自噬和凋亡的调控机制如何？其互调的关键分子是什么？目前尚不清楚。我们前期研究提示，哺乳动物STE20样激酶1（Mammalian Sterile20-like Kinase1, Mst1）抑制自噬，促进凋亡，参与了心肌梗死后左室重构。Lin28a抑制Mst1磷酸化，改善心肌梗死后左室功能，可能通过抑制Mst1降低心肌梗死后心肌损伤。然而，Lin28a/Mst1信号途径是否能够逆转心肌梗死后左室重构的进展？仍需进一步研究阐明。本研究拟采用Lin28a及Mst1转基因鼠、基因敲除小鼠为研究对象，构建心肌梗死模型，揭示Lin28a/ Mst1信号通路在心肌梗死后左室重构中的作用，及在此过程中自噬与凋亡互调的分子机制，为该疾病的防治提供新的思路。

心肌梗死发病率和死亡率一直居高不下，同时伴随而来的心力衰竭等为人熟知的并发症严重影响患者远期生活质量，然而，心梗后调控心脏功能的关键机制目前仍不清楚，阐明心肌梗死后患者死亡率高的分子机制，对于挽救患者的生命有着至关重要的意义。自噬和凋亡是心肌梗死后心脏功能调控的重要机制，其精细调控决定了心肌细胞的损伤程度和心脏功能。哺乳动物STE20样激酶1（哺乳动物STE20样激酶1）是一种丝氨酸/苏氨酸激酶，参与心脏各种病理生理过程，包括调节器官大小，调控自噬、凋亡, 参与了心肌梗死后左室重构。RNA结合蛋白Lin28a抑制Mst1磷酸化，改善心肌梗死后左室功能，可能通过抑制Mst1降低心肌梗死后心肌损伤。然而，Lin28a/Mst1信号途径是否能够逆转心肌梗死后左室重构的进展？仍需进一步研究阐明。本研究的主要发现如下：① 在心肌梗死的条件下，Lin28a可以显著改善心梗后心脏功能，延缓左心室重构; ② Lin28a可以显著促进缺氧后心肌细胞自噬水平、抑制心肌细胞凋亡；③ Lin28a显著抑制Mst1的磷酸化水平；④ Mst1过表达显著恶化心梗后心脏功能，促进心室重构；⑤ Mst1过表达显著抑制心肌细胞缺氧后自噬流水平，促进心肌细胞凋亡。本课题揭示了Lin28a/ Mst1信号通路通过调节心梗条件下心肌细胞自噬与凋亡水平，延缓心脏重构，改善心脏功能的关键机制，为该疾病的防治提供新的思路。