Crucial Role of miR-433 in Regulating Cardiac Fibrosis.
Crucial Role of miR-433 in Regulating Cardiac Fibrosis.
复制标题
miR-433 在调节心脏纤维化中的关键作用。
作者：
Tao L;Bei Y;Chen P;Lei Z;Fu S;Zhang H;Xu J;Che L;Chen X;Sluijter JP;Das S;Cretoiu D;Xu B;Zhong J;Xiao J;Li X
microRNA的失调与许多心血管疾病包括纤维化有关。在这里，我们报告了miR-433在三种心脏疾病模型中持续升高，并伴有显著的心脏纤维化，与心肌细胞相比，miR-433在成纤维细胞中富集。通过EdU掺入、α-SMA染色和纤维化相关基因的表达水平确定，在新生大鼠心脏成纤维细胞中强制表达miR-433可增加增殖及其向肌成纤维细胞的分化。相反，抑制miR-433表现出相反的结果。AZIN 1和JNK 1被鉴定为miR-433的两个靶基因。AZIN 1水平降低激活TGF-β1，而JNK 1下调导致ERK和p38激酶激活，导致Smad 3激活，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（AAV 9）介导的miR-433海绵的心脏转移减轻了心肌梗死后的心脏纤维化和心室功能障碍。因此，我们的工作表明miR-433是改善心脏纤维化的潜在靶点。
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.
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DOI：
10.1073/pnas.1206432109
发表时间：
2012-10-23
影响因子：
11.1
作者：
Bernardo, Bianca C.;Gao, Xiao-Ming;McMullen, Julie R.
通讯作者：
McMullen, Julie R.
中药芪苈强心减轻小鼠急性心肌梗死后心脏重构
影响因子：
4.6
作者：
Tao L;Shen S;Fu S;Fang H;Wang X;Das S;Sluijter JP;Rosenzweig A;Zhou Y;Kong X;Xiao J;Li X
通讯作者：
Li X
影响因子：
5.4
作者：
Karakikes I;Chaanine AH;Kang S;Mukete BN;Jeong D;Zhang S;Hajjar RJ;Lebeche D
通讯作者：
Lebeche D
影响因子：
5
作者：
Aoyama, Yutaka;Kobayashi, Koichi;Murohara, Toyoaki
通讯作者：
Murohara, Toyoaki
影响因子：
10.8
作者：
Peng, Tianqing;Zhang, Ting;Feng, Qingping
通讯作者：
Feng, Qingping