School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Sci Rep. 2018 Mar 16;8(1):4733. doi: 10.1038/s41598-018-23042-w.
Mechanical forces are able to activate hypertrophic growth of cardiomyocytes in the overloaded myocardium. However, the transcriptional profiles triggered by mechanical stretch in cardiac myocytes are not fully understood. Here, we performed the first genome-wide time series study of gene expression changes in stretched cultured neonatal rat ventricular myocytes (NRVM)s, resulting in 205, 579, 737, 621, and 1542 differentially expressed (>2-fold, P < 0.05) genes in response to 1, 4, 12, 24, and 48 hours of cyclic mechanical stretch. We used Ingenuity Pathway Analysis to predict functional pathways and upstream regulators of differentially expressed genes in order to identify regulatory networks that may lead to mechanical stretch induced hypertrophic growth of cardiomyocytes. We also performed micro (miRNA) expression profiling of stretched NRVMs, and identified that a total of 8 and 87 miRNAs were significantly (P < 0.05) altered by 1-12 and 24-48 hours of mechanical stretch, respectively. Finally, through integration of miRNA and mRNA data, we predicted the miRNAs that regulate mRNAs potentially leading to the hypertrophic growth induced by mechanical stretch. These analyses predicted nuclear factor-like 2 (Nrf2) and interferon regulatory transcription factors as well as the let-7 family of miRNAs as playing roles in the regulation of stretch-regulated genes in cardiomyocytes.
机械力能够激活超负荷心肌中的心肌细胞的肥大生长。然而，机械拉伸在心肌细胞中引发的转录谱尚不完全清楚。在这里，我们对拉伸培养的新生大鼠心室肌细胞（NRVM）中的基因表达变化进行了首次全基因组时间序列研究，结果显示，在响应 1、4、12、24 和 48 小时的循环机械拉伸时，有 205、579、737、621 和 1542 个差异表达（>2 倍，P<0.05）基因。我们使用 Ingenuity 通路分析来预测差异表达基因的功能途径和上游调控因子，以确定可能导致心肌细胞机械拉伸诱导的肥大生长的调控网络。我们还对拉伸的 NRVM 进行了微小 RNA（miRNA）表达谱分析，发现总共 8 和 87 个 miRNA 分别被 1-12 和 24-48 小时的机械拉伸显著（P<0.05）改变。最后，通过 miRNA 和 mRNA 数据的整合，我们预测了调节 mRNAs 的 miRNA，这些 mRNAs可能导致机械拉伸诱导的肥大生长。这些分析预测了核因子样 2（Nrf2）和干扰素调节转录因子以及 let-7 家族的 miRNA 在调节心肌细胞中拉伸调节基因中的作用。
