Chaudhari Umesh, Pohjolainen Lotta, Ruskoaho Heikki, Talman Virpi
Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Front Cardiovasc Med. 2023 May 22;10:1148618. doi: 10.3389/fcvm.2023.1148618. eCollection 2023.
After birth, mammalian cardiomyocytes substantially lose proliferative capacity with a concomitant switch from glycolytic to oxidative mitochondrial energy metabolism. Micro-RNAs (miRNAs) regulate gene expression and thus control various cellular processes. Their roles in the postnatal loss of cardiac regeneration are however still largely unclear. Here, we aimed to identify miRNA-gene regulatory networks in the neonatal heart to uncover role of miRNAs in regulation of cell cycle and metabolism.
We performed global miRNA expression profiling using total RNA extracted from mouse ventricular tissue samples collected on postnatal day 1 (P01), P04, P09, and P23. We used the miRWalk database to predict the potential target genes of differentially expressed miRNAs and our previously published mRNA transcriptomics data to identify verified target genes that showed a concomitant differential expression in the neonatal heart. We then analyzed the biological functions of the identified miRNA-gene regulatory networks using enriched Gene Ontology (GO) and KEGG pathway analyses. Altogether 46 miRNAs were differentially expressed in the distinct stages of neonatal heart development. For twenty miRNAs, up- or downregulation took place within the first 9 postnatal days thus correlating temporally with the loss of cardiac regeneration. Importantly, for several miRNAs, including miR-150-5p, miR-484, and miR-210-3p there are no previous reports about their role in cardiac development or disease. The miRNA-gene regulatory networks of upregulated miRNAs negatively regulated biological processes and KEGG pathways related to cell proliferation, while downregulated miRNAs positively regulated biological processes and KEGG pathways associated with activation of mitochondrial metabolism and developmental hypertrophic growth.
This study reports miRNAs and miRNA-gene regulatory networks with no previously described role in cardiac development or disease. These findings may help in elucidating regulatory mechanism of cardiac regeneration and in the development of regenerative therapies.
出生后，哺乳动物心肌细胞的增殖能力大幅丧失，同时伴随着从糖酵解型线粒体能量代谢向氧化型线粒体能量代谢的转变。微小RNA（miRNA）可调节基因表达，从而控制各种细胞过程。然而，它们在出生后心脏再生丧失中的作用仍不清楚。在此，我们旨在识别新生心脏中的miRNA-基因调控网络，以揭示miRNA在细胞周期和代谢调控中的作用。
我们使用从出生后第1天（P01）、P04、P09和P23收集的小鼠心室组织样本中提取的总RNA进行了全基因组miRNA表达谱分析。我们使用miRWalk数据库预测差异表达miRNA的潜在靶基因，并利用我们之前发表的mRNA转录组学数据来识别在新生心脏中同时呈现差异表达的已验证靶基因。然后，我们使用富集的基因本体（GO）和KEGG通路分析来分析所识别的miRNA-基因调控网络的生物学功能。在新生心脏发育的不同阶段，共有46种miRNA差异表达。对于20种miRNA，其上调或下调发生在出生后的前9天内，因此在时间上与心脏再生能力的丧失相关。重要的是，对于几种miRNA，包括miR-150-5p、miR-484和miR-210-3p，此前尚无关于它们在心脏发育或疾病中作用的报道。上调的miRNA的miRNA-基因调控网络对与细胞增殖相关的生物学过程和KEGG通路起负调控作用，而下调的miRNA对与线粒体代谢激活和发育性肥厚生长相关的生物学过程和KEGG通路起正调控作用。
本研究报道了在心脏发育或疾病中此前未描述过作用的miRNA和miRNA-基因调控网络。这些发现可能有助于阐明心脏再生的调控机制以及再生疗法的开发。
