Age-dependent increase of oxidative stress regulates microRNA-29 family preserving cardiac health.
Age-dependent increase of oxidative stress regulates microRNA-29 family preserving cardiac health.
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DOI：
10.1038/s41598-017-16829-w
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发表时间：
2017-12-04
影响因子：
4.6
通讯作者：
Spallotta F
中科院分区：
文献类型：
--
作者：
Heid J;Cencioni C;Ripa R;Baumgart M;Atlante S;Milano G;Scopece A;Kuenne C;Guenther S;Azzimato V;Farsetti A;Rossi G;Braun T;Pompilio G;Martelli F;Zeiher AM;Cellerino A;Gaetano C;Spallotta F
寿命短的绿松石鳉（Nothobranchius furzeri, Nfu）是衰老研究的有效模型。在这里，我们研究了与年龄相关的心脏功能。我们在老化的心脏中观察到氧化应激积累和microRNAs （miRNAs）的参与。5周（幼龄）、12-21周（成年）和28-40周（老年）Nfu心脏的mirna测序显示，随着年龄的增长，23个mirna上调，18个mirna下调。MiR-29家族是衰老过程中上调最多的mirna之一。MiR-29家族的增加导致已知靶标如胶原和DNA甲基转移酶（dnmt）的减少，并伴有5´甲基胞嘧啶（5mC）水平的降低。为了进一步研究miR-29家族在鱼心脏中的作用，我们制作了一个miR-29被敲低的转基因斑马鱼模型。在这个模型中，我们通过转录组分析发现了显著的形态学和功能改变，以及导致缺氧标记上调的氧依赖通路的损伤。为了深入了解miR-29家族可能的缺氧调控，我们将人心脏成纤维细胞暴露于1%的O2水平。在缺氧条件下，我们发现miR-29下调负责胶原和5mC的积累。总体而言，我们的数据表明，miR-29家族上调可能代表了一种内源性机制，旨在改善导致肥大和纤维化的年龄依赖性心脏损伤。
The short-lived turquoise killifish Nothobranchius furzeri (Nfu) is a valid model for aging studies. Here, we investigated its age-associated cardiac function. We observed oxidative stress accumulation and an engagement of microRNAs (miRNAs) in the aging heart. MiRNA-sequencing of 5 week (young), 12–21 week (adult) and 28–40 week (old) Nfu hearts revealed 23 up-regulated and 18 down-regulated miRNAs with age. MiR-29 family turned out as one of the most up-regulated miRNAs during aging. MiR-29 family increase induces a decrease of known targets like collagens and DNA methyl transferases (DNMTs) paralleled by 5´methyl-cytosine (5mC) level decrease. To further investigate miR-29 family role in the fish heart we generated a transgenic zebrafish model where miR-29 was knocked-down. In this model we found significant morphological and functional cardiac alterations and an impairment of oxygen dependent pathways by transcriptome analysis leading to hypoxic marker up-regulation. To get insights the possible hypoxic regulation of miR-29 family, we exposed human cardiac fibroblasts to 1% O2 levels. In hypoxic condition we found miR-29 down-modulation responsible for the accumulation of collagens and 5mC. Overall, our data suggest that miR-29 family up-regulation might represent an endogenous mechanism aimed at ameliorating the age-dependent cardiac damage leading to hypertrophy and fibrosis.
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影响因子：
7.8
作者：
Baumgart M;Groth M;Priebe S;Savino A;Testa G;Dix A;Ripa R;Spallotta F;Gaetano C;Ori M;Terzibasi Tozzini E;Guthke R;Platzer M;Cellerino A
通讯作者：
Cellerino A
影响因子：
3.9
作者：
Graf, Michael;Hartmann, Nils;Englert, Christoph
通讯作者：
Englert, Christoph
影响因子：
--
作者：
Chung HJ;Choi YE;Kim ES;Han YH;Park MJ;Bae IH
通讯作者：
Bae IH
影响因子：
48
作者：
Ebert, Margaret S.;Neilson, Joel R.;Sharp, Phillip A.
通讯作者：
Sharp, Phillip A.
影响因子：
4.8
作者：
Fasanaro, Pasquale;D'Alessandra, Yuri;Martelli, Fabio
通讯作者：
Martelli, Fabio