Downregulation of miR-151-5p contributes to increased susceptibility to arrhythmogenesis during myocardial infarction with estrogen deprivation.
Downregulation of miR-151-5p contributes to increased susceptibility to arrhythmogenesis during myocardial infarction with estrogen deprivation.
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miR-151-5p 的下调导致雌激素剥夺导致的心肌梗死期间心律失常的易感性增加
DOI：
10.1371/journal.pone.0072985
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Shan H
中科院分区：
文献类型：
--
作者：
Zhang Y;Wang R;Du W;Wang S;Yang L;Pan Z;Li X;Xiong X;He H;Shi Y;Liu X;Yu S;Bi Z;Lu Y;Shan H
雌激素缺乏与心血管疾病的发病率增加有关。但单纯的雌激素补充治疗可诱发乳腺癌等严重并发症。本研究旨在阐明雌激素剥夺心肌梗死时心肌梗死易感性增加的分子机制，为雌激素剥夺性心脏病的治疗提供新的靶点。采用冠状动脉结扎加卵巢切除术（OVX）建立了雌激素剥夺的心肌缺血大鼠模型。与非雌激素缺乏大鼠相比，雌激素缺乏大鼠心肌梗死时室性心律失常的易感性和死亡率增加，这与microRNA-151- 5 p（miR-151- 5 p）下调有关。荧光素酶报告基因检测结果表明，miR-151- 5 p可与磷脂酶原（phospholemman，PLM）编码基因FXYD 1的3′-UTR结合，抑制FXYD 1的表达。结果发现，与MI组相比，（OVX+MI）组PLM表达增加。OVX+MI组较单纯MI组出现Kir2.1/IK 1下调、钙超载等变化。将miR-151- 5 p转染到原代培养的心肌细胞中降低PLM水平和[Ca 2 +]i，然而增加Kir2.1水平。这些作用被针对miR-151- 5 p的反义寡核苷酸消除。免疫共沉淀和免疫荧光实验证实了Kir2.1和PLM在大鼠心室组织中的共定位。我们的结论是，增加室性心律失常的脆弱性，在大鼠急性心肌缺血是严重依赖于下调miR-151- 5 p。这些发现支持了miR-151- 5 p可能是预防雌激素缺乏受试者缺血性心律失常的潜在治疗靶点的建议。
Estrogen deficiency is associated with increased incidence of cardiovascular diseases. But merely estrogen supplementary treatment can induce many severe complications such as breast cancer. The present study was designed to elucidate molecular mechanisms underlying increased susceptibility of arrhythmogenesis during myocardial infarction with estrogen deprivation, which provides us a new target to cure cardiac disease accompanied with estrogen deprivation. We successfully established a rat model of myocardial ischemia (MI) accompanied with estrogen deprivation by coronary artery ligation and ovariectomy (OVX). Vulnerability and mortality of ventricular arrhythmias increased in estrogen deficiency rats compared to non estrogen deficiency rats when suffered MI, which was associated with down-regulation of microRNA-151-5p (miR-151-5p). Luciferase Reporter Assay demonstrated that miR-151-5p can bind to the 3′-UTR of FXYD1 (coding gene of phospholemman, PLM) and inhibit its expression. We found that the expression of PLM was increased in (OVX+MI) group compared with MI group. More changes such as down-regulation of Kir2.1/IK1, calcium overload had emerged in (OVX+MI) group compared to MI group merely. Transfection of miR-151-5p into primary cultured myocytes decreased PLM levels and [Ca2+]i, however, increased Kir2.1 levels. These effects were abolished by the antisense oligonucleotides against miR-151-5p. Co-immunoprecipitation and immunofluorescent experiments confirmed the co-localization between Kir2.1 and PLM in rat ventricular tissue. We conclude that the increased ventricular arrhythmias vulnerability in response to acute myocardial ischemia in rat is critically dependent upon down-regulation of miR-151-5p. These findings support the proposal that miR-151-5p could be a potential therapeutic target for the prevention of ischemic arrhythmias in the subjects with estrogen deficiency.
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DOI：
10.1152/ajpheart.00997.2003
发表时间：
2004-04-01
影响因子：
4.8
作者：
Mirza, MA;Zhang, XQ;Cheung, JY
通讯作者：
Cheung, JY
影响因子：
5.6
作者：
Luo, Xiaobin;Xiao, Jiening;Wang, Zhiguo
通讯作者：
Wang, Zhiguo
影响因子：
4.8
作者：
Ahlers, BA;Zhang, XQ;Cheung, JY
通讯作者：
Cheung, JY
影响因子：
10.8
作者：
CURTIS, MJ;WALKER, MJA
通讯作者：
WALKER, MJA
丹参酮 IIA 通过抑制 microRNA-1 预防致命性心律失常引起的心脏性猝死
影响因子：
7.3
作者：
Shan, Hongli;Li, Xuelian;Yang, Baofeng
通讯作者：
Yang, Baofeng