Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.
Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.
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DOI：
10.1161/circulationaha.115.017443
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发表时间：
2016-04-26
期刊：
影响因子：
37.8
通讯作者：
Hill JA
中科院分区：
文献类型：
--
作者：
Li DL;Wang ZV;Ding G;Tan W;Luo X;Criollo A;Xie M;Jiang N;May H;Kyrychenko V;Schneider JW;Gillette TG;Hill JA
阿霉素的临床应用受到心脏毒性的限制。组织病理学改变包括间质心肌纤维化和空泡化心肌细胞的出现。虽然心肌自噬功能失调与多种心血管疾病有关，但自噬在阿霉素心肌病中的作用仍不明确。大多数阿霉素心脏毒性的模型涉及到大剂量的药物注射，这会引起嗜睡、厌食、体重减轻和腹膜纤维化，所有这些都混淆了对自噬的解释。有鉴于此，我们首先建立了一个模型，该模型可以在没有体质症状的情况下引发适度和渐进的心脏毒性，这让人想起在患者身上看到的影响。我们报告阿霉素在体内阻断心肌细胞自噬流量，在培养心肌细胞中阻断自噬流量。伴随这一障碍的是未降解的自溶酶体的强健积累。我们继续将阻塞部位定位为溶酶体酸化中的缺陷。为了测试阿霉素引发的自溶酶体积聚的功能相关性，我们研究了由于Beclin 1单倍体不足而自噬活性降低的动物。Beclin 1+/−小鼠暴露于阿霉素后，心肌结构和功能发生了保护作用。相反，过度表达Beclin 1的动物表现出放大的心脏毒性反应。阿霉素通过损害溶酶体酸化和溶酶体功能来阻断心肌细胞的自噬流量。减少自噬的启动可以预防阿霉素的心脏毒性。
The clinical use of doxorubicin is limited by cardiotoxicity. Histopathologic changes include interstitial myocardial fibrosis and appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity due to haploinsufficiency for Beclin 1. Beclin 1+/− mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals over-expressing Beclin 1 manifested an amplified cardiotoxic response. Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.