The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2
The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2
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DOI：
10.1038/nm1569
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发表时间：
2007-04-01
期刊：
影响因子：
82.9
通讯作者：
Wang, Zhiguo
中科院分区：
文献类型：
--
作者：
Yang, Baofeng;Lin, Huixian;Wang, Zhiguo
microRNA（miRNAs）是内源性非编码RNA，长度约22个核苷酸，通过与靶mRNA 3 '非翻译区的不完全互补序列退火1 -3，介导转录后基因沉默。我们目前对miRNA功能的理解主要依赖于其组织特异性或发育阶段依赖性表达及其进化保守性，因此主要限于其参与发育调控和肿瘤发生（2）。在已经鉴定的超过300种miRNA中，miR-1和miR-133被认为是肌肉特异性的（4-6）。在这里，我们发现miR-1在冠状动脉疾病患者中过表达，并且当在正常或梗死大鼠心脏中过表达时，它会加剧心肌梗死。在梗死大鼠心脏中通过反义抑制剂消除miR-1可缓解心肌梗死。miR-1过表达通过转录后抑制KCNJ 2（编码K+通道亚基Kir2.1）和GJA 1（编码连接蛋白43）减缓传导并使细胞质膜去极化，这可能至少部分解释了其促凋亡潜力。因此，miR-1可能在心脏中具有重要的病理生理功能，并且是潜在的抗心律失常靶点。
MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs1-3. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis(2). Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific(4-6). Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K+ channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.