Tao Lichan, Bei Yihua, Chen Ping, Lei Zhiyong, Fu Siyi, Zhang Haifeng, Xu Jiahong, Che Lin, Chen Xiongwen, Sluijter Joost Pg, Das Saumya, Cretoiu Dragos, Xu Bin, Zhong Jiuchang, Xiao Junjie, Li Xinli
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China.
Theranostics. 2016 Sep 10;6(12):2068-2083. doi: 10.7150/thno.15007. eCollection 2016.
Dysregulation of microRNAs has been implicated in many cardiovascular diseases including fibrosis. Here we report that miR-433 was consistently elevated in three models of heart disease with prominent cardiac fibrosis, and was enriched in fibroblasts compared to cardiomyocytes. Forced expression of miR-433 in neonatal rat cardiac fibroblasts increased proliferation and their differentiation into myofibroblasts as determined by EdU incorporation, α-SMA staining, and expression levels of fibrosis-associated genes. Conversely, inhibition of miR-433 exhibited opposite results. AZIN1 and JNK1 were identified as two target genes of miR-433. Decreased level of AZIN1 activated TGF-β1 while down-regulation of JNK1 resulted in activation of ERK and p38 kinase leading to Smad3 activation and ultimately cardiac fibrosis. Importantly, systemic neutralization of miR-433 or adeno-associated virus 9 (AAV9)-mediated cardiac transfer of a miR-433 sponge attenuated cardiac fibrosis and ventricular dysfunction following myocardial infarction. Thus, our work suggests that miR-433 is a potential target for amelioration of cardiac fibrosis.
微小RNA的失调与包括纤维化在内的许多心血管疾病有关。在此我们报告，在三种具有显著心脏纤维化的心脏病模型中，miR-433持续升高，并且与心肌细胞相比，在成纤维细胞中更为富集。通过EdU掺入、α-SMA染色以及纤维化相关基因的表达水平测定，在新生大鼠心脏成纤维细胞中强制表达miR-433可增加其增殖并促进其向肌成纤维细胞分化。相反，抑制miR-433则表现出相反的结果。AZIN1和JNK1被鉴定为miR-433的两个靶基因。AZIN1水平降低会激活TGF-β1，而JNK1的下调会导致ERK和p38激酶激活，进而导致Smad3激活并最终导致心脏纤维化。重要的是，全身中和miR-433或腺相关病毒9（AAV9）介导的miR-433海绵体心脏转移可减轻心肌梗死后的心脏纤维化和心室功能障碍。因此，我们的研究表明miR-433是改善心脏纤维化的潜在靶点。
