RBFox2-miR-34a-Jph2 axis contributes to cardiac decompensation during heart failure
RBFox2-miR-34a-Jph2 axis contributes to cardiac decompensation during heart failure
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RBFox2-miR-34a-Jph2 轴导致心力衰竭期间心脏代偿失调
DOI：
10.1073/pnas.1822176116
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发表时间：
2019-03-26
影响因子：
11.1
通讯作者：
Fu, Xiang-Dong
中科院分区：
文献类型：
--
作者：
Hu, Jing;Gao, Chen;Fu, Xiang-Dong
心脏性能依赖于高度协调的兴奋-收缩（EC）偶联，并且该关键过程中的缺陷可能因额外的遗传缺陷和/或环境损伤而加剧，从而导致最终的心力衰竭。在这里，我们报告了一个由RNA结合蛋白RBFox 2，应激诱导的microRNA miR-34 a和必需的EC耦合剂JPH 2组成的调控途径。在该途径中，初始心脏缺陷减少RBFox 2表达，这诱导miR-34 a的转录抑制，并且升高的miR-34 a靶向Jph 2以损害EC偶联，这进一步表现出心脏功能障碍，导致进行性心力衰竭。miR-34 a对该过程的关键贡献通过施用其模拟物（其足以诱导心脏缺陷）和通过使用其曲马多缓解RBFox 2消耗诱导的心脏功能障碍来进一步确定。这些发现阐明了一种潜在的前馈机制，以解释向心脏失代偿的关键转变，并提出了一种潜在的治疗心力衰竭的途径。
Heart performance relies on highly coordinated excitation-contraction (EC) coupling, and defects in this critical process may be exacerbated by additional genetic defects and/or environmental insults to cause eventual heart failure. Here we report a regulatory pathway consisting of the RNA binding protein RBFox2, a stress-induced microRNA miR-34a, and the essential EC coupler JPH2. In this pathway, initial cardiac defects diminish RBFox2 expression, which induces transcriptional repression of miR-34a, and elevated miR-34a targets Jph2 to impair EC coupling, which further manifests heart dysfunction, leading to progressive heart failure. The key contribution of miR-34a to this process is further established by administrating its mimic, which is sufficient to induce cardiac defects, and by using its antagomir to alleviate RBFox2 depletion-induced heart dysfunction. These findings elucidate a potential feed-forward mechanism to account for a critical transition to cardiac decompensation and suggest a potential therapeutic avenue against heart failure.