Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis, Health Science Center, Shenzhen University, Shenzhen 518060, China.
Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China.
Int J Mol Sci. 2023 Jan 9;24(2):1283. doi: 10.3390/ijms24021283.
Heart failure is the final stage of various cardiovascular diseases and seriously threatens human health. Increasing mediators have been found to be involved in the pathogenesis of heart failure, including the RNA binding protein RBFox2. It participates in multiple aspects of the regulation of cardiac function and plays a critical role in the process of heart failure. However, how RBFox2 itself is regulated remains unclear. Here, we dissected transcriptomic signatures, including mRNAs and miRNAs, in a mouse model of heart failure after TAC surgery. A global analysis showed that an asymmetric alternation in gene expression and a large-scale upregulation of miRNAs occurred in heart failure. An association analysis revealed that the latter not only contributed to the degradation of numerous mRNA transcripts, but also suppressed the translation of key proteins such as RBFox2. With the aid of Ago2 CLIP-seq data, luciferase assays verified that RBFox2 was targeted by multiple miRNAs, including Let-7, miR-16, and miR-200b, which were significantly upregulated in heart failure. The overexpression of these miRNAs suppressed the RBFox2 protein and its downstream effects in cardiomyocytes, which was evidenced by the suppressed alternative splicing of the Enah gene and impaired E-C coupling via the repression of the Jph2 protein. The inhibition of Let-7, the most abundant miRNA family targeting RBFox2, could restore the RBFox2 protein as well as its downstream effects in dysfunctional cardiomyocytes induced by ISO treatment. In all, these findings revealed the molecular mechanism leading to RBFox2 depression in heart failure, and provided an approach to rescue RBFox2 through miRNA inhibition for the treatment of heart failure.
心力衰竭是各种心血管疾病的终末阶段，严重威胁人类健康。越来越多的介质被发现参与心力衰竭的发病机制，包括 RNA 结合蛋白 RBFox2。它参与心脏功能调节的多个方面，在心衰过程中起着关键作用。然而，RBFox2 本身是如何被调节的仍不清楚。在这里，我们在 TAC 手术后的心力衰竭小鼠模型中分析了转录组特征，包括 mRNA 和 miRNA。全局分析显示，心力衰竭时发生了基因表达的不对称改变和 miRNA 的大规模上调。关联分析显示，后者不仅有助于许多 mRNA 转录物的降解，而且还抑制了 RBFox2 等关键蛋白的翻译。借助 Ago2 CLIP-seq 数据，荧光素酶测定验证了 RBFox2 被多个 miRNA 靶向，包括 Let-7、miR-16 和 miR-200b，这些 miRNA 在心力衰竭中显著上调。这些 miRNA 的过表达抑制了心肌细胞中 RBFox2 蛋白及其下游效应，这表现在 Enah 基因的选择性剪接受到抑制，以及通过 Jph2 蛋白的抑制导致 E-C 偶联受损。Let-7 是靶向 RBFox2 的最丰富的 miRNA 家族，其抑制可恢复 ISO 处理诱导的功能失调心肌细胞中 RBFox2 蛋白及其下游效应。总之，这些发现揭示了导致心力衰竭中 RBFox2 抑制的分子机制，并提供了一种通过 miRNA 抑制来挽救 RBFox2 以治疗心力衰竭的方法。
