血管發(fā)育是胚胎發(fā)育的重要過程，研究血管發(fā)育的分子機(jī)制有重要的生理和病理意義。microRNA-126是內(nèi)皮細(xì)胞特異表達(dá)的微小RNA(miRNA),，參與調(diào)節(jié)血管生成和維持血管完整性，但其具體作用機(jī)制尚待進(jìn)一步闡明,。
荊清研究員研究組與劉廷析研究員研究組合作,，利用斑馬魚作為模式生物，發(fā)現(xiàn)在斑馬魚基因組內(nèi)存在兩個miR-126位點（miR-126a/b）,，可在體外和體內(nèi)產(chǎn)生成熟有生物活性的miRNA,。這一研究成果公布在Circulation Research雜志上。
研究發(fā)現(xiàn)miR-126a/b參與調(diào)節(jié)胚胎血管完整性,，且有協(xié)同效應(yīng),。進(jìn)一步研究表明，miR-126a/b通過調(diào)節(jié)內(nèi)皮細(xì)胞中pak1的表達(dá)水平達(dá)到調(diào)節(jié)血管完整性目的,。該研究拓寬了對內(nèi)皮細(xì)胞miRNA功能的認(rèn)識,，有助于闡明miRNA調(diào)節(jié)血管發(fā)育的作用機(jī)制和深入探索結(jié)構(gòu)性血管疾病的發(fā)病機(jī)理。
今年六月,，荊清研究員研究組還深入研究了microRNA-1 (miR-1) 在心肌肥厚中的作用及其調(diào)控機(jī)制,，發(fā)現(xiàn)miR-1是心臟中表達(dá)豐度最高的miRNA,，且特異表達(dá)于心肌細(xì)胞。這一研究成果公布在國際學(xué)術(shù)期刊 Journal of Cell Science 上,。
心肌肥厚是心臟在受到各種生理刺激,，組織損傷或者內(nèi)分泌失調(diào)的情況下產(chǎn)生的肥厚性生長。心肌肥厚在功能上是一個初始的適應(yīng)性反應(yīng),，有助于增大心臟的收縮力,，維持心臟血輸出量，但是持續(xù)的肥厚最終會導(dǎo)致心衰和猝死,。因此對心肌肥厚的發(fā)病機(jī)制的研究一直是生命科學(xué)研究的熱點問題,。最近研究表明，一種新的基因調(diào)控因子,，microRNA (miRNA),，參與了心肌肥厚的發(fā)生發(fā)展過程。然而,，目前對miRNA在心肌肥厚過程中的作用及機(jī)制研究尚處于起步階段,，有待于進(jìn)一步闡明。
在這篇文章中,，研究人員深入研究了microRNA-1 (miR-1) 在心肌肥厚中的作用及其調(diào)控機(jī)制,。該研究發(fā)現(xiàn)miR-1是心臟中表達(dá)豐度最高的miRNA，且特異表達(dá)于心肌細(xì)胞,。進(jìn)一步研究發(fā)現(xiàn)在心肌肥厚過程中,，miR-1的表達(dá)水平下調(diào)，并證明了miR-1具有抑制心肌細(xì)胞肥大的作用,。重要的是,，該研究進(jìn)一步確認(rèn)了一個細(xì)胞骨架結(jié)合蛋白twinfilin-1是miR-1的一個靶基因，并且首次報道了該蛋白具有促進(jìn)心肌細(xì)胞肥大的作用,。
這些結(jié)果表明心臟在受到肥厚性刺激后,，miR-1水平的降低引起twinfilin-1的表達(dá)上調(diào)，從而通過調(diào)控心肌細(xì)胞骨架導(dǎo)致心肌肥厚,。該研究不僅拓寬了對心肌肥厚分子機(jī)制的認(rèn)識,，有助于闡明miRNA調(diào)控心肌肥厚的分子機(jī)制，并且為心肌疾病的治療提供了新的理論依據(jù)和潛在靶點,，具有較強(qiáng)的理論意義和應(yīng)用價值,。相關(guān)研究目前已申請專利。（生物谷Bioon.com）
生物谷推薦原文出處：
Circulation Research doi: 10.1161/CIRCRESAHA.110.225045
Two Functional MicroRNA-126s Repress a Novel Target Gene p21-Activated Kinase 1 to Regulate Vascular Integrity in Zebrafish
Jun Zou ; Wen-Qing Li ; Qing Li ; Xiang-Qi Li ; Jun-Tao Zhang ; Gan-Qiang Liu ; Jian Chen ; Xiao-Xu Qiu ; Fu-Ju Tian ; Zhi-Zhang Wang ; Ni Zhu ; Yong-Wen Qin ; Bairong Shen ; Ting Xi Liu *; and Qing Jing *
From the Key Laboratory of Stem Cell Biology (J.Z., W.-Q.L., Q.L., X.-Q.L., J.-T.Z., J.C., X.-X.Q., F.-J.T., Z.-Z.W., T.X.L., Q.J.), Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao-Tong University School of Medicine, Shanghai; Department of Cardiology (N.Z., Y.-W.Q., Q.J.), Changhai Hospital, Shanghai; Suzhou University (B.S); Tongji University (G.-Q.L, B.S.), Shanghai; and Graduate School of Chinese Academy of Sciences (J.Z., Q.L., J.C., X.-X.Q., F.-J.T.), China.
* To whom correspondence should be addressed. E-mail: [email protected] or [email protected].
Rationale: MicroRNAs (miRNAs) are key regulators of vascular development and diseases. The function and underlying mechanism of endothelial miRNAs have not been fully defined.
Objective: To investigate the role of endothelial miR-126 in zebrafish vascular development.
Methods and Results: Two homologs of miR-126, miR-126a (namely miR-126 in previous literature) and miR-126b, with only 1 nucleotide difference in their mature sequences, were identified in zebrafish genome. In vitro analysis showed that both precursors could sufficiently produce mature functional miRNAs. Expression analyses by Northern blot and quantitative RT-PCR showed that both miR-126s accumulated significantly 12 hours after fertilization and were specifically expressed in endothelial cells of zebrafish. Inhibition of miR-126a or miR-126b with specific morpholinos caused cranial hemorrhage, and simultaneous inhibition of both miR-126s resulted in a pronounced hemorrhage in higher percentage of embryos. Bioinformatics prediction showed that the targets of miR-126a/b partially overlapped but essentially differed. p21-activated kinase1 (pak1) was identified as a novel target of miR-126a/b, and pak1 3' untranslated region was differently regulated by these 2 miRNAs. Quantitative RT-PCR, in situ hybridization, and Western blot analyses showed that the level of pak1 was reduced when miR-126a/b were overexpressed. Notably, pak1 expression in endothelial cells was increased when miR-126a/b were knocked down. Furthermore, overexpression of the active form of human pak1 caused cranial hemorrhage, and knockdown pak1 effectively rescued the hemorrhage caused by inhibiting miR-126a/b.
Conclusions: Two functional endothelial cell–specific miRNAs, miR-126a and miR-126b, synergistically regulate zebrafish vascular integrity, and pak1 is a critical target of miR-126a/b in vascular development.
Key words: miR-126 ? pak1 ? vascular development ? zebrafish
