Transcription Factor GATA4 Inhibits Doxorubicin-induced Autophagy and Cardiomyocyte Death
Transcription Factor GATA4 Inhibits Doxorubicin-induced Autophagy and Cardiomyocyte Death
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DOI：
10.1074/jbc.m109.070037
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发表时间：
2010-01-01
影响因子：
4.8
通讯作者：
Liang, Qiangrong
中科院分区：
文献类型：
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作者：
Kobayashi, Satoru;Volden, Paul;Liang, Qiangrong
阿霉素（DOX）是一种有效的抗肿瘤药物，已知会导致心力衰竭。转录因子GATA 4拮抗DOX诱导的心脏毒性。然而，保护机制仍然模糊不清。自噬是溶酶体降解长寿命蛋白质和细胞器的主要细胞途径，其激活可能是保护性的或有害的，这取决于特定的病理生理条件。在这里，我们研究了GATA 4抑制自噬的能力，作为其保护新生大鼠心肌细胞免受DOX毒性的潜在机制。DOX显著增加心肌细胞中的自噬通量，如在不存在和存在溶酶体抑制剂巴弗洛霉素A1的情况下LC 3-II（微管相关蛋白轻链3形式2）的蛋白水平或自噬空泡数目的差异所示。通过多种测定确定的DOX诱导的心肌细胞死亡被激活自噬的药物或遗传方法加重，但它被抑制自噬的操作减弱，表明自噬有助于DOX心脏毒性。DOX处理耗尽了GATA 4蛋白水平，这使心肌细胞易受DOX毒性影响。事实上，GATA 4基因沉默引发了自噬，使DOX更具毒性，而GATA 4过表达抑制了DOX诱导的自噬，减少了心肌细胞死亡。从机制上讲，GATA 4上调了生存因子Bcl 2的基因表达，并抑制了DOX诱导的自噬相关基因的激活，这可能是GATA 4的抗凋亡和抗自噬作用的原因。总之，这些发现表明自噬的激活介导DOX心脏毒性，并且GATA 4的保存通过调节Bcl 2和自噬相关基因的表达来抑制自噬从而减弱DOX心脏毒性。
Doxorubicin (DOX) is a potent anti-tumor drug known to cause heart failure. The transcription factor GATA4 antagonizes DOX-induced cardiotoxicity. However, the protective mechanism remains obscure. Autophagy is the primary cellular pathway for lysosomal degradation of long-lived proteins and organelles, and its activation could be either protective or detrimental depending on specific pathophysiological conditions. Here we investigated the ability of GATA4 to inhibit autophagy as a potential mechanism underlying its protection against DOX toxicity in cultured neonatal rat cardiomyocytes. DOX markedly increased autophagic flux in cardiomyocytes as indicated by the difference in protein levels of LC3-II (microtubule-associated protein light chain 3 form 2) or numbers of autophagic vacuoles in the absence and presence of the lysosomal inhibitor bafilomycin A1. DOX-induced cardiomyocyte death determined by multiple assays was aggravated by a drug or genetic approach that activates autophagy, but it was attenuated by manipulations that inhibit autophagy, suggesting that autophagy contributes to DOX cardiotoxicity. DOX treatment depleted GATA4 protein levels, which predisposed cardiomyocytes to DOX toxicity. Indeed, GATA4 gene silencing triggered autophagy that rendered DOX more toxic, whereas GATA4 overexpression inhibited DOX-induced autophagy, reducing cardiomyocyte death. Mechanistically, GATA4 up-regulated gene expression of the survival factor Bcl2 and suppressed DOX-induced activation of autophagy-related genes, which may likely be responsible for the anti-apoptotic and anti-autophagic effects of GATA4. Together, these findings suggest that activation of autophagy mediates DOX cardiotoxicity, and preservation of GATA4 attenuates DOX cardiotoxicity by inhibiting autophagy through modulation of the expression of Bcl2 and autophagy-related genes.