Overexpression of microRNA-1 impairs cardiac contractile function by damaging sarcomere assembly
Overexpression of microRNA-1 impairs cardiac contractile function by damaging sarcomere assembly
复制标题
microRNA-1 的过度表达通过破坏肌节组装来损害心脏收缩功能。
DOI：
10.1093/cvr/cvs196
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发表时间：
2012-08-01
影响因子：
10.8
通讯作者：
Yang, Bao-Feng
中科院分区：
文献类型：
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作者：
Ai, Jing;Zhang, Rong;Yang, Bao-Feng
本研究采用实时荧光定量逆转录聚合酶链反应（real-time reverse transcriptionpolymerase chain reaction，RT-PCR）技术，建立心肌特异性过表达miR-1的转基因（Tg）小鼠（C57 BL/6）模型，探讨过表达miR-1对心肌收缩功能的影响及其可能的分子机制。通过压力-容积环分析，我们发现Tg小鼠的心功能随年龄的增长而下降。组织学分析和电子显微镜显示短肌节与透明区和H区的损失，以及肌原纤维断裂和潮解在Tg小鼠。进一步的研究表明，miR-1通过靶向MYLK 3、CALM 1和CALM 2基因的3UTR下调钙调蛋白（CaM）和心肌肌球蛋白轻链激酶（cMLCK）蛋白的表达，导致肌球蛋白轻链2 v（MLC 2 v）和心肌肌球蛋白结合蛋白-C（cMyBP-C）的磷酸化减少。锁核酸修饰的反义miR-1（LNA-antimiR-1）基因敲低miR-1可减轻miR-1过表达引起的心功能不良变化，miR-1可诱导心肌结构重构，损害心肌收缩功能。靶向cMLCK和CaM可能是miR-1对与收缩机制相关的肌肉结构组分的有害影响的基础。我们的研究提供了第一个证据表明miRNAs会导致心脏的不良结构重塑。
The purpose of the present study was to evaluate the effects of overexpression of microRNA-1 (miR-1) on cardiac contractile function and the potential molecular mechanisms.Transgenic (Tg) mice (C57BL/6) for cardiac-specific overexpression of miR-1 driven by the -myosin heavy chain promoter were generated and identified by real-time reverse-transcription polymerase chain reaction with left ventricular samples. We found an age-dependent decrease in the heart function in Tg mice by pressurevolume loop analysis. Histological analysis and electron microscopy displayed short sarcomeres with the loss of the clear zone and H-zone as well as myofibril fragmentation and deliquescence in Tg mice. Further studies demonstrated miR-1 post-transcriptionally down-regulated the expression of calmodulin (CaM) and cardiac myosin light chain kinase (cMLCK) proteins by targeting the 3UTRs of MYLK3, CALM1, and CALM2 genes, leading to decreased phosphorylations of myosin light chain 2v (MLC2v) and cardiac myosin binding protein-C (cMyBP-C). Knockdown of miR-1 by locked nucleic acid-modified anti-miR-1 antisense (LNA-antimiR-1) mitigated the adverse changes of cardiac function associated with overexpression of miR-1.miR-1 induces adverse structural remodelling to impair cardiac contractile function. Targeting cMLCK and CaM likely underlies the detrimental effects of miR-1 on structural components of muscles related to the contractile machinery. Our study provides the first evidence that miRNAs cause adverse structural remodelling of the heart.