Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice
Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice
复制标题
心肌细胞过度表达 miR-27b 诱导小鼠心脏肥大和功能障碍
DOI：
10.1038/cr.2011.132
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发表时间：
2012-03-01
期刊：
影响因子：
44.1
通讯作者：
Yang, Xiao
中科院分区：
文献类型：
--
作者：
Wang, Jian;Song, Yao;Yang, Xiao
最近的研究已经开始揭示microRNAs（miRNAs）在心脏肥大和功能障碍的发病机制中的关键作用。在这项研究中，我们测试了转化生长因子-β（TGF-β）调节的miRNA是否在心脏肥大和心力衰竭（HF）的发展中发挥了关键作用。我们观察到miR-27 b在心肌细胞特异性Smad 4敲除小鼠的心脏中上调，这些小鼠发生了心脏肥大。体外实验表明，TGF-β 1可抑制miR-27 b的表达，其过表达可促进肥大细胞的生长，而抑制miR-27 b可抑制苯肾上腺素（PE）处理引起的肥大细胞生长。此外，对心肌细胞特异性过表达miR-27 b的转基因小鼠的分析表明，miR-27 b过表达足以诱导心脏肥大和功能障碍。我们验证了过氧化物酶体增殖物激活受体-γ（PPAR-gamma）作为心肌细胞中miR-27 b的直接靶点。一致地，miR-27 b转基因小鼠显示出比对照小鼠显著更低的PPAR-gamma水平。此外，在压力超负荷诱导的HF小鼠模型中，使用特定的阿托伐他汀在体内沉默miR-27 b增加了心脏PPAR-gamma表达，减轻了心脏肥大和功能障碍。我们的研究结果表明，TGF-β 1调控的miR-27 b参与了心肌肥大的调控，并验证了miR-27 b作为心脏疾病的有效治疗靶点。
Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. In this study, we tested whether a transforming growth factor-beta (TGF-beta)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-beta 1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. We validated the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) as a direct target of miR-27b in cardiomyocyte. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-gamma than the control mice. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-gamma expression, attenuated cardiac hypertrophy and dysfunction. The results of our study demonstrate that TGF-beta 1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases.