Long noncoding RNA Cfast regulates cardiac fibrosis.
Long noncoding RNA Cfast regulates cardiac fibrosis.
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长非编码RNA Cfast调节心脏纤维化
DOI：
10.1016/j.omtn.2020.11.013
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发表时间：
2021-03-05
期刊：
影响因子：
--
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Zhang F;Fu X;Kataoka M;Liu N;Wang Y;Gao F;Liang T;Dong X;Pei J;Hu X;Zhu W;Yu H;Cowan DB;Hu X;Huang ZP;Wang J;Wang DZ;Chen J
心脏纤维化发生在大多数心脏疾病中，其降低心肌顺应性，损害心脏收缩和舒张功能，并最终导致心力衰竭。长链非编码RNA（lncRNA）近年来已成为多种生物学过程的重要调控因子，但其在心肌纤维化中的表达和功能尚不清楚。在心肌梗死（MI）小鼠模型中使用无偏转录组分析，我们鉴定了一种心脏成纤维细胞富集的lncRNA（AK 048087），称为心脏成纤维细胞相关转录本（Cfast），MI后显著升高。通过小干扰RNA（siRNA）或慢病毒短发夹RNA（shRNA）沉默Cfast表达导致纤维化相关基因表达的抑制和肌成纤维细胞向心脏成纤维细胞的转分化。在小鼠心脏中通过慢病毒shRNA消耗Cfast显著减弱由MI或异丙肾上腺素输注诱导的心脏纤维化。重要的是，抑制Cfast可改善心脏损伤后的心脏功能。RNA下拉，然后质谱分析确定COTL 1（coactosin-like 1）作为Cfast相互作用蛋白之一。从机制上讲，Cfast竞争性抑制COTL 1与TRAP 1（转化生长因子-β受体相关蛋白1）的相互作用，TRAP 1通过增加SMAD 2/SMAD 4复合物的形成来增强TGF-β信号传导。因此，我们的研究确定Cfast作为一种新的心脏成纤维细胞富集的lncRNA，调节心脏成纤维细胞激活响应病理生理应激。Cfast可作为预防心脏纤维化和心脏疾病的潜在治疗靶点。在这里，我们描述了一种新的心脏成纤维细胞富集的lncRNA称为Cfast，它调节心脏成纤维细胞的激活和纤维化，以响应心脏中的病理生理应激。Cfast可作为预防心脏疾病纤维化的潜在治疗靶点。
Cardiac fibrosis occurs in most cardiac diseases, which reduces cardiac muscle compliance, impairs both systolic and diastolic heart function and, ultimately, leads to heart failure. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of a variety of biological processes; however, little is known about the expression and function of lncRNAs in cardiac fibrosis. Using unbiased transcriptome profiling in a mouse model of myocardial infarction (MI), we identified a cardiac fibroblast-enriched lncRNA (AK048087) named cardiac fibroblast-associated transcript (Cfast), which is significantly elevated after MI. Silencing Cfast expression by small interfering RNAs (siRNAs) or lentiviral short hairpin RNAs (shRNAs) resulted in suppression of fibrosis-related gene expression and transdifferentiation of myofibroblasts into cardiac fibroblasts. Depletion of Cfast by lentiviral shRNAs in mouse hearts significantly attenuated cardiac fibrosis induced by MI or isoproterenol-infusion. Importantly, inhibition of Cfast ameliorated cardiac function following cardiac injury. RNA pull-down followed by mass spectrometry analyses identified COTL1 (coactosin-like 1) as one of the Cfast interacting proteins. Mechanistically, Cfast competitively inhibits the COTL1 interaction with TRAP1 (transforming growth factor-β receptor-associated protein 1), which enhances TGF-β signaling by augmenting SMAD2/SMAD4 complex formation. Therefore, our study identifies Cfast as a novel cardiac fibroblast-enriched lncRNA that regulates cardiac fibroblast activation in response to pathophysiological stress. Cfast could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases. Here, we describe a novel cardiac fibroblast-enriched lncRNA called Cfast, which regulates cardiac fibroblast activation and fibrosis in response to pathophysiological stress in the heart. Cfast could serve as a potential therapeutic target for the prevention of fibrosis in cardiac diseases.
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影响因子：
1.8
作者：
Li G;Yin Y;Chen J;Fan Y;Ma J;Huang Y;Chen C;Dai P;Chen S;Zhao S
通讯作者：
Zhao S
影响因子：
17.1
作者：
Micheletti R;Plaisance I;Abraham BJ;Sarre A;Ting CC;Alexanian M;Maric D;Maison D;Nemir M;Young RA;Schroen B;González A;Ounzain S;Pedrazzini T
通讯作者：
Pedrazzini T
影响因子：
16.6
作者：
Jaiswal, Jyoti K.;Lauritzen, Stine P.;Scheffer, Luana;Sakaguchi, Masakiyo;Bunkenborg, Jakob;Simon, Sanford M.;Kallunki, Tuula;Jaattela, Marja;Nylandsted, Jesper
通讯作者：
Nylandsted, Jesper
影响因子：
14.8
作者：
Lim, Semi;Cho, Hye Young;Kim, Sunghoon
通讯作者：
Kim, Sunghoon
DOI：
10.1073/pnas.96.5.1881
发表时间：
1999-03-02
影响因子：
11.1
作者：
Provost, P;Samuelsson, B;Rådmark, O
通讯作者：
Rådmark, O