MicroRNAs add a new dimension to cardiovascular disease.
MicroRNAs add a new dimension to cardiovascular disease.
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DOI：
10.1161/circulationaha.109.889048
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发表时间：
2010-03-02
期刊：
影响因子：
37.8
通讯作者：
Olson EN
中科院分区：
文献类型：
--
作者：
Small EM;Frost RJ;Olson EN
在发达国家，心血管疾病是人类发病率和死亡率的主要原因。因此，为了开发新的诊断和治疗策略来对抗心血管疾病，人们致力于确定患病心脏和血管的分子和病理生理学特征。多个研究小组的共同工作揭示了一个复杂的转录和转录后调节电路，其完整性对于维持心脏内稳态至关重要。目前，各种转录和转录后调控因子的突变或异常表达与人类心脏疾病相关，而对这些靶基因活性的药理调节是目前研究的主要焦点。最近，一类新的非编码小RNA，称为microRNAs(MiRNAs)，被认为是重要的转录和转录后基因表达抑制因子，被认为可以“微调”靶信使RNAs(MRNAs)的翻译输出。1、2miRNAs与多种心血管疾病的发病机制有关，已成为治疗干预的重要靶点。本文综述了与心血管疾病相关的miRNAs的基本生物学和作用机制，并阐述了miRNAs在心血管疾病治疗中作为靶向治疗的可能性。MiRNA加工和功能miRNAs来自较长的前体RNA，称为初级miRNAs，受传统转录因子调控，由RNA聚合酶II转录。初级miRNAs长数百至数千个核苷酸，在细胞核中被RNaseIII酶DROSHA和双链RNA结合蛋白Dgcr8加工成70至100个核苷酸的发夹状前体miRNA。然后，前体miRNA被核出口因子exportin 5转运到细胞质中，并被RNaseIII酶Disher进一步加工成19到25个核苷酸的双链RNA。然后，这种双链miRNA被掺入RNA诱导的沉默复合体中。一条链留在RNA诱导的沉默复合体中，成为“成熟”的miRNA，而另一条链通常迅速降解，被称为“星”链(miRNA*)。当被装载到RNA诱导的沉默复合体中时，成熟的miRNA与靶mRNAs结合，通过促进mRNA降解或抑制翻译起到负调控基因表达的作用。3翻译抑制似乎是哺乳动物的主要机制；然而，在蛋白质水平上强烈下调的靶基因往往显示出mRNA水平的降低，4这表明mRNA的不稳定是导致基因沉默的主要原因。成熟的miRNA通常通过与具有互补序列的mRNA的3个非翻译区(UTR)结合来调节基因表达，尽管新的证据表明miRNAs也可能针对5个UTRs或外显子，甚至可能与调节DNA序列进行碱基配对来调节转录。在miRNA与3非编码区的结合中，mRNA3的降解和/或翻译抑制的程度受到多种机制的影响，包括miRNA与靶mRNA之间的整体互补性、相邻序列的二级结构、miRNA结合位点到mRNA编码序列的距离以及3非编码区内靶点的数量。5.miRNA2至8核苷酸之间的互补，称为…
Cardiovascular disease is the predominant cause of human morbidity and mortality in developed countries. Thus, extraordinary effort has been devoted to determining the molecular and pathophysiological characteristics of the diseased heart and vasculature with the goal of developing novel diagnostic and therapeutic strategies to combat cardiovascular disease. The collective work of multiple research groups has uncovered a complex transcriptional and posttranscriptional regulatory circuit, the integrity of which is essential for the maintenance of cardiac homeostasis. Mutations in or aberrant expression of various transcriptional and posttranscriptional regulators have now been correlated with human cardiac disease, and pharmacological modulation of the activity of these target genes is a major focus of ongoing research. Recently, a novel class of small noncoding RNAs, called microRNAs (miRNAs), was identified as important transcriptional and posttranscriptional inhibitors of gene expression thought to “fine tune” the translational output of target messenger RNAs (mRNAs). 1, 2 miRNAs are implicated in the pathogenesis of various cardiovascular diseases and have become an intriguing target for therapeutic intervention. This review focuses on the basic biology and mechanism of action of miRNAs specifically pertaining to cardiovascular disorders and addresses the potential for miRNAs to be targeted therapeutically in the treatment of cardiovascular disease. miRNA Processing and Function miRNAs originate from longer precursor RNAs called primary miRNAs that are regulated by conventional transcription factors and transcribed by RNA polymerase II. Primary miRNAs are hundreds to thousands of nucleotides long and are processed in the nucleus into an 70-to 100-nucleotide hairpin-shaped precursor miRNA by the RNase III enzyme Drosha and the double-stranded RNA binding protein DGCR8. The precursor miRNA is then transported into the cytoplasm by the nuclear export factor exportin 5 and further processed into an 19-to 25-nucleotide double-stranded RNA by the RNaseIII enzyme Dicer. This duplex miRNA is then incorporated into the RNA-induced silencing complex. One strand remains in the RNA-induced silencing complex and becomes the “mature” miRNA, whereas the other strand is often rapidly degraded and is called the “star” strand (miRNA*). On being loaded into the RNA-induced silencing complex, the mature miRNA associates with target mRNAs and acts as a negative regulator of gene expression by promoting mRNA degradation or inhibiting translation. 3 Translational inhibition seems to be the predominant mechanism in mammals; however, target genes that are strongly downregulated on the protein level often show a reduced mRNA level, 4 suggesting that mRNA destabilization is a major contributor to gene silencing. A mature miRNA typically regulates gene expression via an association with the 3 untranslated region (UTR) of an mRNA with complementary sequence, although emerging evidence suggests that miRNAs may also target 5 UTRs or exons and may potentially even undergo base pairing with regulatory DNA sequences to regulate transcription. On miRNA binding to a 3 UTR, the degree of mRNA degradation and/or translational repression is affected by multiple mechanisms, including the overall complementarity between the miRNA and target mRNA, the secondary structure of the adjacent sequences, the distance of the miRNA binding site to the coding sequence of the mRNA, and the number of target sites within the 3 UTR. 5 Complementarity between nucleotides 2 through 8 of the miRNA, called the …