Inhibition of Histone Deacetylases Prevents Cardiac Remodeling After Myocardial Infarction by Restoring Autophagosome Processing in Cardiac Fibroblasts
Inhibition of Histone Deacetylases Prevents Cardiac Remodeling After Myocardial Infarction by Restoring Autophagosome Processing in Cardiac Fibroblasts
复制标题
组蛋白脱乙酰酶的抑制通过恢复心脏成纤维细胞中的自噬体处理来预防心肌梗死后的心脏重塑
DOI：
10.1159/000493672
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发表时间：
2018-09
影响因子：
--
通讯作者：
Jifeng Xu
中科院分区：
文献类型：
--
作者：
Yaping Wang;Panpan Chen;Lihan Wang;Jing Zhao;Zhiwei Zhong;Yingchao Wang;Jifeng Xu
背景/目的：组蛋白去乙酰化酶（HDAC）在基因转录、心脏发育和疾病的调控中起着关键作用。本研究的目的是探讨抑制HDAC是否能改善小鼠心肌梗死（MI）模型的心脏重塑及其潜在机制。研究方法：在C57/BL小鼠MI后，通过每天腹膜内注射给予HDAC抑制剂阿司他汀A（TSA，0.1mg/kg/天），连续8周。采用超声心动图和组织病理学检查评估心功能。体外培养新生大鼠心脏成纤维细胞（NRCFs），模拟缺氧。使用串联荧光mCherry-GFP-LC 3测定法测量自噬通量。Western blot检测自噬生物标志物。结果：8周后，体内HDAC的抑制导致心脏重构改善，从而改善心室功能。MI与LC 3-II表达增加和自噬衔接蛋白p62积累相关，表明自噬通量受损，TSA治疗可逆转。体外模拟缺氧后，培养的NRCFs表现出增加的细胞死亡。通过点状双荧光mCherry-绿色荧光蛋白串联标记轻链-3表达评估，细胞死亡增加与自噬体数量显著增加相关，但与自溶酶体数量无关，表明缺氧导致自噬通量受损。重要的是，TSA治疗逆转了缺氧诱导的受损的自噬通量，并导致细胞死亡减少40%。这是伴随着改善线粒体膜电位。TSA治疗的有益作用被靶向LAMP 2的RNAi干预消除;同样，体内递送氯喹消除了TSA介导的心脏保护作用。结论：我们的研究结果提供了HDAC抑制剂TSA预防MI后心脏重塑的证据，并且依赖于恢复心脏成纤维细胞的自噬体加工。
Background/Aims: Histone deacetylases (HDACs) play a critical role in the regulation of gene transcription, cardiac development, and diseases. The aim of this study was to investigate whether the inhibition of HDACs improves cardiac remodeling and its underlying mechanisms in a mouse myocardial infarction (MI) model. Methods: The HDAC inhibitor trichostatin A (TSA, 0.1 mg/kg/day) was administered via daily intraperitoneal injections for 8 consecutive weeks after MI in C57/BL mice. Echocardiography and tissue histopathology were used to assess cardiac function. Cultured neonatal rat cardiac fibroblasts (NRCFs) were subjected to simulated hypoxia in vitro. Autophagic flux was measured using the tandem fluorescent mCherry-GFP-LC3 assay. Western blot was used to detect autophagic biomarkers. Results: After 8 weeks, the inhibition of HDACs in vivo resulted in improved cardiac remodeling and hence better ventricular function. MI was associated with increased LC3-II expression and the accumulation of autophagy adaptor protein p62, indicating impaired autophagic flux, which was reversed by TSA treatment. Cultured NRCFs exhibited increased cell death after simulated hypoxia in vitro. Increased cell death was associated with markedly increased numbers of autophagosomes but not autolysosomes, as assessed by punctate dual fluorescent mCherry-green fluorescent protein tandem-tagged light chain-3 expression, indicating that hypoxia resulted in impaired autophagic flux. Importantly, TSA treatment reversed hypoxia-induced impaired autophagic flux and led to a 40% decrease in cell death. This was accompanied by improved mitochondrial membrane potential. The beneficial effects of TSA therapy were abolished by RNAi intervention targeting LAMP2; likewise, in vivo delivery of chloroquine abolished the TSA-mediated cardioprotective effects. Conclusion: Our results provide evidence that the HDAC inhibitor TSA prevents cardiac remodeling after MI and is dependent on restoring autophagosome processing of cardiac fibroblasts.
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DOI：
10.1016/j.bbamcr.2010.04.007
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Zhao TC;Zhang LX;Cheng G;Liu JT
通讯作者：
Liu JT
脂肪来源的循环 miRNA 调节其他组织中的基因表达。
影响因子：
64.8
作者：
Thomou T;Mori MA;Dreyfuss JM;Konishi M;Sakaguchi M;Wolfrum C;Rao TN;Winnay JN;Garcia-Martin R;Grinspoon SK;Gorden P;Kahn CR
通讯作者：
Kahn CR
影响因子：
37.8
作者：
Xiucui Ma;Rebecca J. Godar;A. Diwan
通讯作者：
Xiucui Ma;Rebecca J. Godar;A. Diwan
影响因子：
10.8
作者：
Kanamori, Hiromitsu;Takemura, Genzou;Minatoguchi, Shinya
通讯作者：
Minatoguchi, Shinya
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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