Autophagic program is regulated by miR-325
Autophagic program is regulated by miR-325
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DOI：
10.1038/cdd.2014.18
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发表时间：
2014-06-01
影响因子：
12.4
通讯作者：
Pei-Feng, L.
中科院分区：
文献类型：
--
作者：
Bo, L.;Su-Ling, D.;Pei-Feng, L.
自噬是维持心肌细胞内稳态所必需的。然而，这种异常的自噬可能会导致心力衰竭的发展。自噬在心肌缺血/再灌流过程中增强，自噬的分子调控机制尚待阐明。我们在这里报道了miR-325、ARC和E2F1组成了一个调节自噬的轴。我们的结果表明，在缺氧/复氧和缺血/再灌注过程中，miR-325的表达上调。心肌细胞特异性过表达miR-325增强自噬反应和心肌梗死范围，而敲除miR-325则抑制自噬和细胞死亡。我们搜索了miR-325的下游介体，并确定ARC是miR-325的靶标。ARC转基因小鼠可以减少压力超负荷导致的心力衰竭时的自噬和心肌梗死范围，而ARC基因缺失的小鼠心脏中的自噬积聚增加。MiR-325对ARC的抑制导致其不能抑制自噬程序。在探讨miR-325表达调控的分子机制中，我们的结果显示转录因子E2F1促进了miR-325的表达。E2F1基因缺失的小鼠在缺血/再灌流时自噬和心肌梗死范围减少。我们的研究揭示了一个新的自噬调控模型，该模型由E2F1、miR-325和ARC组成。调节它们的水平可能为治疗心力衰竭提供一种新的方法。
Autophagy is required for the maintenance of cardiomyocytes homeostasis. However, the abnormal autophagy could lead to the development of heart failure. Autophagy is enhanced during myocardial ischemia/reperfusion; it remains to elucidate the molecular regulation of autophagy. We report here that miR-325, ARC and E2F1 constitute an axis that regulates autophagy. Our results showed that miR-325 expression is upregulated upon anoxia/reoxygenation and ischemia/ reperfusion. Cardiomyocytespecific overexpression of the miR-325 potentiates autophagic responses and myocardial infarct sizes, whereas knockdown of miR-325 inhibited autophagy and cell death. We searched for the downstream mediator of miR-325 and identified that ARC is a target of miR-325. ARC transgenic mice could attenuate autophagy and myocardial infarction sizes upon pressure-overloadinduced heart failure, whereas ARC null mice exhibited an increased autophagic accumulation in the heart. The suppression of ARC by miR-325 led to its inability to repress autophagic program. In exploring the molecular mechanism by which miR-325 expression is regulated, our results revealed that the transcription factor E2F1 contributed to promote miR-325 expression. E2F1 null mice demonstrated reduced autophagy and myocardial infarction sizes upon ischemia/ reperfusion. Our present study reveals a novel autophagic regulating model that is composed of E2F1, miR-325 and ARC. Modulation of their levels may provide a new approach for tackling cardiac failure.