MicroRNA-103/107 Regulate Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury Through Targeting FADD
MicroRNA-103/107 Regulate Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury Through Targeting FADD
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MicroRNA-103/107 通过靶向 FADD 调节程序性坏死和心肌缺血/再灌注损伤
DOI：
10.1161/circresaha.117.305781
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发表时间：
2015-07-31
影响因子：
20.1
通讯作者：
Li, Pei-feng
中科院分区：
文献类型：
--
作者：
Wang, Jian-Xun;Zhang, Xiao-Jie;Li, Pei-feng
原理：坏死是心脏病中心肌细胞死亡的主要形式之一。最近的研究表明，某些类型的坏死是受调控和编程依赖于受体相互作用丝氨酸/苏氨酸蛋白激酶（RIPK）1和3的激活，这可能是负调控Fas相关蛋白与死亡结构域（FADD）。目的：本研究旨在验证microRNA-103/107和H19通过靶向FADD参与调控RIPK 1和RIPK 3依赖的H9 c2细胞坏死和心肌梗死的假说。方法：我们的研究结果表明，FADD通过影响H9 c2细胞中RIPK 1和RIPK 3复合物的形成参与H2 O2诱导的坏死。我们进一步证明了miR-103/107直接靶向FADD。miR-103/107的敲低拮抗细胞模型中的坏死以及小鼠缺血/再灌注模型中的心肌梗死。miR-103/107-FADD通路不参与肿瘤坏死因子-a诱导的坏死。在探索miR-103/107调控的分子机制中，我们发现长链非编码RNA H19直接与miR-103/107结合并调控FADD的表达和necross.Conclusions：我们的结果揭示了一种新的心肌坏死调控模型，该模型由H19、miR-103/107和FADD组成。调节它们的水平可能为预防心肌坏死提供新的途径。
Rationale: Necrosis is one of the main forms of cardiomyocyte death in heart disease. Recent studies have demonstrated that certain types of necrosis are regulated and programmed dependent on the activation of receptorinteracting serine/threonine-protein kinase (RIPK) 1 and 3 which may be negatively regulated by Fas-associated protein with death domain (FADD). In addition, microRNAs and long noncoding RNAs have been shown to play important roles in various biological processes recently.Objective: The purpose of this study was to test the hypothesis that microRNA-103/107 and H19 can participate in the regulation of RIPK1-and RIPK3-dependent necrosis in fetal cardiomyocyte-derived H9c2 cells and myocardial infarction through targeting FADD.Methods and Results: Our results show that FADD participates in H2O2 -induced necrosis by influencing the formation of RIPK1 and RIPK3 complexes in H9c2 cells. We further demonstrate that miR-103/107 target FADD directly. Knockdown of miR-103/107 antagonizes necrosis in the cellular model and also myocardial infarction in a mouse ischemia/reperfusion model. The miR-103/107-FADD pathway does not participate in tumor necrosis factor-a-induced necrosis. In exploring the molecular mechanism by which miR-103/107 are regulated, we show that long noncoding RNA H19 directly binds to miR-103/107 and regulates FADD expression and necrosis.Conclusions: Our results reveal a novel myocardial necrosis regulation model, which is composed of H19, miR-103/107, and FADD. Modulation of their levels may provide a new approach for preventing myocardial necrosis.