Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis
Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis
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DOI：
10.1073/pnas.0805038105
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发表时间：
2008-09-02
影响因子：
11.1
通讯作者：
Olson, Eric N.
中科院分区：
文献类型：
--
作者：
van Rooij, Eva;Sutherland, Lillian B.;Olson, Eric N.
冠状动脉闭塞导致的急性心肌梗死（MI）伴有病理性重塑反应，包括心肌肥大性生长和纤维化，这会损害心肌收缩力。此前，我们发现心肌肥大和心力衰竭伴随着一组特定微小RNA（miRNA）表达的特征性变化，这些miRNA作为基因表达的负调控因子。在此，我们表明小鼠和人类的心肌梗死也会导致特定miRNA的失调，这些miRNA与参与心肌肥大和心力衰竭的miRNA相似但又有所不同。在受心肌梗死调控的miRNA中，有miR - 29家族的成员，它们在梗死相邻区域的心脏中表达下调。miR - 29家族靶向一组编码参与纤维化的蛋白质的mRNA，包括多种胶原蛋白、原纤维蛋白和弹性蛋白。因此，预计miR - 29的下调会解除对这些mRNA表达的抑制并增强纤维化反应。事实上，在体外和体内用抗miR抑制miR - 29会诱导胶原蛋白的表达，而在成纤维细胞中过表达miR - 29会降低胶原蛋白的表达。我们得出结论，miR - 29作为心脏纤维化的调节因子，总体上是组织纤维化的一个潜在治疗靶点。
Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.