Haploinsufficiency of target of rapamycin attenuates cardiomyopathies in adult zebrafish.
Haploinsufficiency of target of rapamycin attenuates cardiomyopathies in adult zebrafish.
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DOI：
10.1161/circresaha.111.248260
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发表时间：
2011-09-02
影响因子：
20.1
通讯作者：
Xu X
中科院分区：
文献类型：
--
作者：
Ding Y;Sun X;Huang W;Hoage T;Redfield M;Kushwaha S;Sivasubbu S;Lin X;Ekker S;Xu X
虽然雷帕霉素(TOR)信号抑制靶点的心脏保护作用已被用于雷帕霉素的药理学研究，但遗传证据仍然缺乏。在这里，我们探索成年斑马鱼作为一种新的脊椎动物模型来解剖心肌病的信号通路。我们建立了第二只成年斑马鱼阿霉素(DOX)诱导的心肌病模型。通过对DOX和我们以前建立的贫血诱导的心肌病模型的遗传学分析，我们的目标是破译TOR信号在不同病因的心肌病中的功能。随着两种心肌病模型的发展，我们检测了发病不同阶段的动态TOR活性以及TOR信号抑制的不同效果。然而，在两种模型中，通过短期雷帕霉素治疗抑制TOR信号可以有效地减轻心脏增大。为了评估降低TOR的长期效果，我们利用了从插入突变筛选中鉴定出的雷帕霉素(Ztor)突变体的斑马鱼。我们发现，在两种成年FISH心肌病模型中，ZTOR杂合子FISH中的TOR单倍体不足改善了心功能，防止了病理性重构事件，并最终降低了死亡率。从机制上讲，这些心肌保护作用是通过抑制TOR信号的抗肥大、抗凋亡和自噬作用来实现的。我们的结果证明成年斑马鱼是人类心肌病的保守的新的脊椎动物模型。此外，我们提供了第一个遗传学证据，证明TOR信号抑制对至少两种不同病因的心肌病具有长期的心脏保护作用，尽管在它们的发病机制中有动态的TOR活性。
Although a cardioprotective function of target of rapamycin (TOR) signaling inhibition has been suggested by pharmacological studies using rapamycin, genetic evidences are still lacking. Here, we explored adult zebrafish as a novel vertebrate model for dissecting signaling pathways in cardiomyopathy. We generate the second adult zebrafish cardiomyopathy model induced by doxorubicin (DOX). By genetically analyzing both the DOX and our previous established anemia-induced cardiomyopathy models, we aim to decipher the functions of TOR signaling in cardiomyopathies of different etiology. Along the progression of both cardiomyopathy models, we detected dynamic TOR activity at different stages of pathogenesis as well as distinct effects of TOR signaling inhibition. Nevertheless, cardiac enlargement in both models can be effectively attenuated by inhibition of TOR signaling via short-term rapamycin treatment. To assess the long term effects of TOR reduction, we utilized a zebrafish target of rapamycin (ztor) mutant identified from an insertional mutagenesis screen. We show that TOR haploinsufficiency in the ztor heterozygous fish improved cardiac function, prevented pathological remodeling events, and ultimately reduced mortality in both adult fish models of cardiomyopathy. Mechanistically, these cardioprotective effects are conveyed by the anti-hypertrophy, anti-apoptosis, and proautophagy function of TOR signaling inhibition. Our results prove adult zebrafish as a conserved novel vertebrate model for human cardiomyopathies. Moreover, we provide the first genetic evidence to demonstrate a long-term cardioprotective effect of TOR signaling inhibition on at least two cardiomyopathies of distinct etiology, despite dynamic TOR activities during their pathogenesis.