Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses
Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses
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DOI：
10.1093/eurheartj/ehw001
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发表时间：
2017-05-07
影响因子：
39.3
通讯作者：
Yang, Burton B.
中科院分区：
文献类型：
--
作者：
Du, William W.;Yang, Weining;Yang, Burton B.
环状RNA是在哺乳动物细胞中检测到的非编码RNA的一个亚类。本研究的目的是测试的作用，一个环状RNA的circ-Foxo 3在衰老中使用在体外和体内的approaches.Methods和结果使用分子和细胞生物学的方法，我们表明，环状RNA产生的叉头家族成员的转录因子，Foxo 3，即circ-Foxo 3，是高度表达在心脏样本的老年患者和小鼠，这与细胞衰老的标志物有关。阿霉素诱导的心肌病因circ-Foxo 3的异位表达而加重，但因内源性circ-Foxo 3的沉默而减轻。我们还发现，沉默circ-Foxo 3抑制小鼠胚胎成纤维细胞的衰老和circ-Foxo 3的异位表达诱导衰老。结果发现circ-Foxo 3主要分布在细胞质中，并与抗衰老蛋白ID-1、转录因子E2 F1以及抗应激蛋白FAK和HIF 1 α相互作用。结论ID-1、E2 F1、FAK和HIF 1 α与circ-Foxo 3相互作用后，保留在细胞质中，不再发挥其抗衰老和抗应激作用。导致细胞衰老增加。
Aims Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches.Methods and results Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor E2F1, as well as the anti-stress proteins FAK and HIF1 alpha.Conclusion We conclude that ID-1, E2F1, FAK, and HIF1 alpha interact with circ-Foxo3 and are retained in the cytoplasm and could no longer exert their anti-senescent and anti-stress roles, resulting in increased cellular senescence.