atg7-Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity.
atg7-Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity.
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基于ATG7的自噬激活逆转阿霉素引起的心脏毒性。
DOI：
10.1161/circresaha.121.319104
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发表时间：
2021-10
影响因子：
20.1
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Wang Y;Lu X;Wang X;Qiu Q;Zhu P;Ma L;Ma X;Herrmann J;Lin X;Wang W;Xu X
蒽环类药物所致的心脏毒性(AIC)是限制其作为有效化疗药物使用的主要副作用。当心功能恶化时，没有基于机制的治疗方法可用。我们的目标是阐明AIC的动态自噬缺陷，并通过遗传学和药理学研究确定一种基于机制的治疗。通过对成年AIC(AAIC)斑马鱼模型的表型分析，我们检测到了自噬的两个阶段的反应：早期激活，后期抑制，以心功能下降为特征。我们对编码限速自噬核心蛋白的ATG7进行了条件遗传学研究，发现ATG7的过度表达(OE)在AAIC的晚期有治疗作用，但在早期有有害的影响。然后，我们使用胚胎AIC(EAIC)斑马鱼模型评估了37种FDA批准的自噬激活剂(FAAs)的治疗效果，并确定螺内酯、普伐他汀和米诺地尔为最好的药物。我们在AAIC模型中验证了这些药物的治疗效果，证实了这些药物在AIC的晚期发挥了治疗作用，但在AIC的早期没有发挥作用。最后，我们证明了时间依赖的治疗效应在小鼠AIC模型中是保守的，螺内酯和雷帕霉素以ATG7依赖的方式激活自噬。我们的研究结果表明，基于ATG7的自噬激活是逆转AIC心功能下降的有效治疗途径，突显了基于自噬的治疗的时间依赖性。
Anthracycline-induced cardiotoxicity (AIC) is a major side effect that limits the use of anthracyclines as effective chemotherapeutics. No mechanism-based therapy is available when cardiac function deteriorates. We aim to elucidate the dynamic autophagic defects in AIC, and to identify a mechanism-based therapy via both genetic and pharmacological studies. Through phenotyping an adult AIC (aAIC) zebrafish model, we detected a biphasic response in autophagy: activation in the early stage and suppression in the later phase that is characterized by a decline in cardiac function. We conducted conditional genetic studies with atg7, which encodes a rate-limiting autophagy core protein, and found that atg7 overexpression (OE) leads to therapeutic effects in the late phase but deleterious effects in the early phase of aAIC. We then assessed the therapeutic effects of 37 FDA-approved autophagy activators (FAAs) using an embryonic AIC (eAIC) zebrafish model and identified spironolactone, pravastatin, and minoxidil as top-ranking drugs. We demonstrated the therapeutic efficacy of these FAAs in the aAIC model and confirmed that these drugs exert therapeutic effects in the late phase but not in the early AIC phase. Finally, we demonstrated that the time-dependent therapeutic effects are conserved in a mouse AIC model and that spironolactone and rapamycin activated autophagy in an Atg7-dependent fashion. Our findings suggest that atg7-based autophagy activation is an effective therapeutic avenue to reversing the decline in cardiac function in AIC, highlighting the time dependent nature of autophagy-based therapy.