Hubrecht Institute, Royal Netherlands Academy of Sciences, PO Box 85164, Utrecht, The Netherlands.
Nat Cell Biol. 2010 Dec;12(12):1220-7. doi: 10.1038/ncb2126. Epub 2010 Nov 21.
MicroRNAs (miRs) are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length. Increasing evidence implicates miRs in myocardial disease processes. Here we show that miR-199b is a direct calcineurin/NFAT target gene that increases in expression in mouse and human heart failure, and targets the nuclear NFAT kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a (Dyrk1a), constituting a pathogenic feed forward mechanism that affects calcineurin-responsive gene expression. Mutant mice overexpressing miR-199b, or haploinsufficient for Dyrk1a, are sensitized to calcineurin/NFAT signalling or pressure overload and show stress-induced cardiomegaly through reduced Dyrk1a expression. In vivo inhibition of miR-199b by a specific antagomir normalized Dyrk1a expression, reduced nuclear NFAT activity and caused marked inhibition and even reversal of hypertrophy and fibrosis in mouse models of heart failure. Our results reveal that microRNAs affect cardiac cellular signalling and gene expression, and implicate miR-199b as a therapeutic target in heart failure.
MicroRNAs (miRs) 是一类约 22 个核苷酸长的单链非编码 RNA。越来越多的证据表明，miRs 参与了心肌疾病的发生发展过程。在这里，我们发现 miR-199b 是钙调神经磷酸酶/NFAT 的直接靶基因，在小鼠和人类心力衰竭中表达增加，并靶向核 NFAT 激酶双特异性酪氨酸-(Y)-磷酸化调节激酶 1a（Dyrk1a），构成影响钙调神经磷酸酶反应性基因表达的致病正反馈机制。过表达 miR-199b 的突变小鼠或 Dyrk1a 杂合不足的小鼠对钙调神经磷酸酶/NFAT 信号或压力超负荷更为敏感，并通过减少 Dyrk1a 表达表现出应激诱导的心脏增大。通过特异性反义核苷酸抑制体内 miR-199b，可使 Dyrk1a 的表达正常化，降低核 NFAT 活性，并显著抑制甚至逆转心力衰竭小鼠模型中的肥大和纤维化。我们的研究结果表明，miRNAs 影响心脏细胞的信号转导和基因表达，并提示 miR-199b 是心力衰竭的治疗靶点。
