HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction
HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction
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DOI：
10.1016/j.ebiom.2018.12.003
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发表时间：
2019-01-01
期刊：
影响因子：
11.1
通讯作者：
Wang, Zhong
中科院分区：
文献类型：
--
作者：
Tian, Shuo;Lei, Ienglam;Wang, Zhong
背景：表观遗传组蛋白乙酰化是控制细胞代谢、分化和修复等功能的重要事件。在这里，我们的目的是确定是否丙戊酸（VPA），FDA批准的组蛋白去乙酰化双相障碍的抑制剂，可以保护心脏免受心肌梗死（MI）的损伤和阐明关键的分子pathways.Methods：VPA给药MI大鼠在不同的时间点，发病和MI损伤后。超声心动图，组织学，血清生物学测定，和基因表达，抑制和过度表达进行表征的收缩功能，梗死面积，基因和信号转导pathways.Findings：VPA治疗减少了梗死面积-50't和保存心脏的收缩功能后，急性MI大鼠。即使在梗死后60分钟，VPA治疗也显著降低了梗死面积。长期应用VPA可明显改善心肌功能。VPA调节细胞存活和抗炎反应所必需的基因表达。因此，VPA处理后氧化应激和细胞死亡显著减少。此外，Foxml被确定为VPA的潜在关键靶标。Foxml的过表达提供了与VPA治疗相似的心脏保护作用。特别是，VPA治疗和Foxml过表达都抑制了MI后的炎症反应，以保护心脏。相反，Foxml活性的抑制消除了VPA的心脏保护作用。VPA通过Foxml上调介导的CM保护作用也在人ESC衍生的CM缺氧再灌注系统中被鉴定。解释：VPA治疗显著减少MI后的心脏损伤，并且VPA的心脏保护作用可能通过Foxml途径介导。基金：本工作主要得到1 R 01 HL 109054的支持。(C)2018作者由爱思唯尔公司出版
Background: Epigenetic histone acetylation is a major event controlling cell functions, such as metabolism, differentiation and repair. Here, we aim to determine whether Valproic acid (VPA), a FDA approved inhibitor of histone deacetylation for bipolar disease, could protect heart against myocardial infarction (MI) injury and elucidate key molecular pathways.Methods: VPA was administrated to Ml rats at different time points, onset and after MI injury. Echocardiography, histology, serum biology assays, and gene expression, inhibition, and over-expression were performed to characterize the systolic function, infarct size, gene and signaling pathways.Findings: VPA treatment reduced the infarct size by-50't and preserved the systolic function of heart after acute Ml in rats. Even 60 min after infarction, VPA treatment significantly decreased infarct size. furthermore, longterm treatment of VPA markedly improved myocardial performance. VPA regulated gene expression essential for cell survival and anti-inflammatory response. Consequently, oxidative stress and cell death were notably reduced after VPA treatment. Moreover, Foxml was identified as a potential key target of VPA. Overexpression of Foxml provided similar heart protective effect to VPA treatment. Particularly, both VPA treatment and Foxml over-expression repressed inflammatory response after MI for heart protection. In contrast, inhibition of Foxml activity abolished the cardiac protective effect of VPA. VPA mediated CM protection through Foxml up regulation was also identified in a human ESC derived CM hypoxiaireperfusion system.Interpretation: VPA treatments significantly reduce cardiac damage after MI and the cardioprotect ve effect of VPA is likely mediated via Foxml pathway. Fund: This work was mainly supported by 1R01HL109054. (C) 2018 The Authors. Published by Elsevier B.V.