MIAT Is a Pro-fibrotic Long Non-coding RNA Governing Cardiac Fibrosis in Post-infarct Myocardium.
MIAT Is a Pro-fibrotic Long Non-coding RNA Governing Cardiac Fibrosis in Post-infarct Myocardium.
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MIAT 是一种促纤维化长非编码 RNA，可控制梗塞后心肌纤维化。
DOI：
10.1038/srep42657
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发表时间：
2017-02-15
影响因子：
4.6
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Qu X;Du Y;Shu Y;Gao M;Sun F;Luo S;Yang T;Zhan L;Yuan Y;Chu W;Pan Z;Wang Z;Yang B;Lu Y
一种长非编码 RNA (lncRNA)，称为心肌梗塞相关转录本 (MIAT)，已被证明会带来心肌梗塞 (MI) 的风险。本研究的目的是阐明 MIAT 在调节心脏纤维化中的病理生理学作用。在MI小鼠模型中，我们发现MIAT显着上调，并伴有心脏间质纤维化。 MI 中 MIAT 的上调伴随着一些纤维化相关调节因子的失调：miR-24 的下调以及 Furin 和 TGF-β1 的上调。最值得注意的是，通过 siRNA 敲低内源性 MIAT 可减少心脏纤维化，改善心脏功能，并恢复纤维化相关调节因子的失调表达。在用血清或血管紧张素 II 处理的心脏成纤维细胞中，一致观察到类似的 MIAT 上调和 miR-24 下调。这些变化促进了成纤维细胞增殖和胶原蛋白积累，而通过 siRNA 敲低 MIAT 或过表达 miR-24 及其模拟物则消除了纤维形成。因此，我们的研究确定 MIAT 是心脏中第一个促纤维化的 lncRNA，并揭示了 MIAT 在 MI 发病机制中的作用。这些发现还表明，MIAT 水平正常化可能被证明是治疗 MI 诱发的心脏纤维化和相关心脏功能障碍的一种治疗选择。
A long non-coding RNA (lncRNA), named myocardial infarction associated transcript (MIAT), has been documented to confer risk of myocardial infarction (MI). The aim of this study is to elucidate the pathophysiological role of MIAT in regulation of cardiac fibrosis. In a mouse model of MI, we found that MIAT was remarkably up-regulated, which was accompanied by cardiac interstitial fibrosis. MIAT up-regulation in MI was accompanied by deregulation of some fibrosis-related regulators: down-regulation of miR-24 and up-regulation of Furin and TGF-β1. Most notably, knockdown of endogenous MIAT by its siRNA reduced cardiac fibrosis and improved cardiac function and restored the deregulated expression of the fibrosis-related regulators. In cardiac fibroblasts treated with serum or angiotensin II, similar up-regulation of MIAT and down-regulation of miR-24 were consistently observed. These changes promoted fibroblasts proliferation and collagen accumulation, whereas knockdown of MIAT by siRNA or overexpression of miR-24 with its mimic abrogated the fibrogenesis. Our study therefore has identified MIAT as the first pro-fibrotic lncRNA in heart and unraveled the role of MIAT in the pathogenesis of MI. These findings also promise that normalization of MIAT level may prove to be a therapeutic option for the treatment of MI-induced cardiac fibrosis and the associated cardiac dysfunction.