Hao Yuanyuan, Lu Qun, Yang Guodong, Ma Aiqun
Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Shaanxi Key Laboratory of Molecular Cardiology (Xi'an Jiaotong University), Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Shaanxi 710061, China.
Biochem Biophys Res Commun. 2016 Oct 28;479(4):833-840. doi: 10.1016/j.bbrc.2016.09.122. Epub 2016 Sep 28.
Myocardial remodeling and cardiac dysfunction prevention may represent a therapeutic approach to reduce mortality in patients with myocardial infarction (MI). We investigated the effects of Lin28a in experimental MI models, as well as the mechanisms underlying these effects.
Left anterior descending (LAD) coronary artery ligation was used to construct an MI-induced injury model. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of Lin28a against MI-induced injury.
Lin28a significantly inhibited left ventricular remodeling and cardiac dysfunction after MI, as demonstrated via echocardiography and hemodynamic measurements. Lin28a reduced cardiac enzyme and inflammatory marker release in mice subjected to MI-induced injury. The mechanisms underlying the protective effects of Lin28a against MI-induced injury were associated with autophagy enhancements and apoptosis inhibition. Consistent with these findings, Lin28a knockdown aggravated cardiac remodeling and dysfunction after MI-induced injury. Lin28a knockdown also inhibited cardiomyocyte autophagy and increased cardiomyocyte apoptosis in mice subjected to MI-induced injury. Interestingly, Sirt1 knockdown abolished the protective effects of Lin28a against cardiac remodeling and dysfunction after MI, and Lin28a failed to increase the numbers of GFP-LC3-positive punctae and decrease aggresome and p62 accumulation in Sirt1-knockdown neonatal cardiomyocytes subjected to hypoxia-induced injury.
Lin28a inhibits cardiac remodeling, improves cardiac function, and reduces cardiac enzyme and inflammatory marker release after MI. Lin28a also up-regulates cardiomyocyte autophagy and inhibits cardiomyocyte apoptosis through Sirt1 activation.
心肌重塑和心脏功能障碍的预防可能是降低心肌梗死（MI）患者死亡率的一种治疗方法。我们研究了Lin28a在实验性MI模型中的作用及其作用机制。
采用左冠状动脉前降支（LAD）结扎构建MI诱导损伤模型。分离并培养新生心肌细胞，以研究Lin28a对MI诱导损伤的保护作用机制。
经超声心动图和血流动力学测量证实，Lin28a显著抑制MI后的左心室重塑和心脏功能障碍。Lin28a减少了MI诱导损伤小鼠的心肌酶和炎症标志物释放。Lin28a对MI诱导损伤的保护作用机制与自噬增强和凋亡抑制有关。与这些发现一致，Lin28a基因敲低加重了MI诱导损伤后的心脏重塑和功能障碍。Lin28a基因敲低还抑制了MI诱导损伤小鼠的心肌细胞自噬并增加了心肌细胞凋亡。有趣的是，Sirt1基因敲低消除了Lin28a对MI后心脏重塑和功能障碍的保护作用，并且在缺氧诱导损伤的Sirt1基因敲低新生心肌细胞中，Lin28a未能增加GFP-LC3阳性斑点数量并减少聚集体和p62积累。
Lin28a抑制MI后的心脏重塑，改善心脏功能，并减少心肌酶和炎症标志物释放。Lin28a还通过激活Sirt1上调心肌细胞自噬并抑制心肌细胞凋亡。
