Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy.
Department of Biosciences, University of Milan, 20122 Milan, Italy.
Cells. 2023 Nov 5;12(21):2578. doi: 10.3390/cells12212578.
Noncoding RNAs (ncRNAs), which include circular RNAs (circRNAs) and microRNAs (miRNAs), regulate the development of cardiovascular diseases (CVD). Notably, circRNAs can interact with miRNAs, influencing their specific mRNA targets' levels and shaping a competing endogenous RNAs (ceRNA) network. However, these interactions and their respective functions remain largely unexplored in ischemic heart failure (IHF). This study is aimed at identifying circRNA-centered ceRNA networks in non-end-stage IHF. Approximately 662 circRNA-miRNA-mRNA interactions were identified in the heart by combining state-of-the-art bioinformatics tools with experimental data. Importantly, KEGG terms of the enriched mRNA indicated CVD-related signaling pathways. A specific network centered on circBPTF was validated experimentally. The levels of let-7a-5p, miR-18a-3p, miR-146b-5p, and miR-196b-5p were enriched in circBPTF pull-down experiments, and circBPTF silencing inhibited the expression of and , which are targets of miR-196b-5p. Furthermore, as suggested by the enriched pathway terms of the circBPTF ceRNA network, circBPTF inhibition elicited endothelial cell cycle arrest. circBPTF expression increased in endothelial cells exposed to hypoxia, and its upregulation was confirmed in cardiac samples of 36 end-stage IHF patients compared to healthy controls. In conclusion, circRNAs act as miRNA sponges, regulating the functions of multiple mRNA targets, thus providing a novel vision of HF pathogenesis and laying the theoretical foundation for further experimental studies.
非编码 RNA（ncRNA），包括环状 RNA（circRNA）和 microRNA（miRNA），调节心血管疾病（CVD）的发展。值得注意的是，circRNA 可以与 miRNA 相互作用，影响其特定 mRNA 靶标水平，并形成竞争性内源 RNA（ceRNA）网络。然而，这些相互作用及其各自的功能在缺血性心力衰竭（IHF）中仍很大程度上未被探索。本研究旨在鉴定非终末期 IHF 中以 circRNA 为中心的 ceRNA 网络。通过将最先进的生物信息学工具与实验数据相结合，在心脏中鉴定了大约 662 个 circRNA-miRNA-mRNA 相互作用。重要的是，富集 mRNA 的 KEGG 术语表明了与 CVD 相关的信号通路。一个以 circBPTF 为中心的特定网络在实验中得到了验证。在 circBPTF 下拉实验中富集了 let-7a-5p、miR-18a-3p、miR-146b-5p 和 miR-196b-5p 的水平，circBPTF 沉默抑制了 和 的表达，它们是 miR-196b-5p 的靶标。此外，正如 circBPTF ceRNA 网络的富集途径术语所表明的那样，circBPTF 抑制引起内皮细胞周期停滞。在暴露于缺氧的内皮细胞中，circBPTF 的表达增加，并且在与健康对照相比的 36 例终末期 IHF 患者的心脏样本中证实了其上调。总之，circRNA 作为 miRNA 海绵发挥作用，调节多个 mRNA 靶标的功能，从而为 HF 发病机制提供了新的视角，并为进一步的实验研究奠定了理论基础。
