5-Aminolevulinic acid with sodium ferrous citrate induces autophagy and protects cardiomyocytes from hypoxia-induced cellular injury through MAPK-Nrf-2-HO-1 signaling cascade.
5-Aminolevulinic acid with sodium ferrous citrate induces autophagy and protects cardiomyocytes from hypoxia-induced cellular injury through MAPK-Nrf-2-HO-1 signaling cascade.
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DOI：
10.1016/j.bbrc.2016.09.156
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发表时间：
2016-10
影响因子：
3.1
通讯作者：
Mingyi Zhao;P. Zhu;M. Fujino;Yoshiaki Nishio;Jimei Chen;Hidenori Ito;Kiwamu Takahashi;M. Nakajima;Tohru Tanaka;Lingling Zhao;Zhuang Jian;Xiao‐Kang Li
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文献类型：
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作者：
Mingyi Zhao;P. Zhu;M. Fujino;Yoshiaki Nishio;Jimei Chen;Hidenori Ito;Kiwamu Takahashi;M. Nakajima;Tohru Tanaka;Lingling Zhao;Zhuang Jian;Xiao‐Kang Li
研究背景缺氧通过氧化应激和线粒体功能障碍引起心脏疾病。5-氨基乙酰丙酸联合柠檬酸亚铁钠（ALA/SFC）可上调血红素氧合酶-1（HO-1）表达，减少巨噬细胞浸润和肾细胞凋亡。然而，其基本机制在很大程度上仍然未知。材料与方法用ALA/SFC预处理小鼠心房肌HL-1细胞，然后暴露于缺氧中。结果ALA/SFC预处理显著减轻缺氧诱导的心肌细胞凋亡、活性氧产生和线粒体损伤，同时增加细胞活力和自噬水平。ALA/SFC诱导的HO-1表达与Nrf-2的上调和核转位相关，而Nrf-2 siRNA显著降低HO-1的表达。ERK 1/2、p38和SAPK/JNK通路被ALA/SFC激活，它们的特异性抑制剂显著降低ALA/SFC介导的HO-1上调。沉默Nrf-2或HO-1及自噬抑制剂LY 294002均能抑制ALA/AFC对缺氧损伤的保护作用，并降低ALA/SFC诱导的自噬。结论ALA/SFC通过激活MAPK/Nrf-2/HO-1信号通路诱导自噬，保护缺氧诱导的心肌细胞凋亡。
BackgroundHypoxia causes cardiac disease via oxidative stress and mitochondrial dysfunction. 5-Aminolevulinic acid in combination with sodium ferrous citrate (ALA/SFC) has been shown to up-regulate heme oxygenase-1 (HO-1) and decrease macrophage infiltration and renal cell apoptosis in renal ischemia injury mice. However, its underlying mechanism remains largely unknown. The aim of this study was to investigate whether ALA/SFC could protect cardiomyocytes from hypoxia-induced apoptosis by autophagy via HO-1 signaling.Materials & methodsMurine atrial cardiomyocyte HL-1 cells were pretreated with ALA/SFC and then exposed to hypoxia.ResultsALA/SFC pretreatment significantly attenuated hypoxia-induced cardiomyocyte apoptosis, reactive oxygen species production, and mitochondrial injury, while it increased cell viability and autophagy levels. HO-1 expression by ALA/SFC was associated with up-regulation and nuclear translocation of Nrf-2, whereas Nrf-2 siRNA dramatically reduced HO-1 expression. ERK1/2, p38, and SAPK/JNK pathways were activated by ALA/SFC and their specific inhibitors significantly reduced ALA/SFC-mediated HO-1 upregulation. Silencing of either Nrf-2 or HO-1and LY294002, inhibitor of autophagy, abolished the protective ability of ALA/AFC against hypoxia-induced injury and reduced ALA/SFC-induced autophagy.ConclusionTaken together, our data suggest that ALA/SFC induces autophagy via activation of MAPK/Nrf-2/HO-1 signaling pathway to protect cardiomyocytes from hypoxia-induced apoptosis.