近日,，中南大學(xué)麻醉醫(yī)學(xué)研究所教授徐軍美領(lǐng)導(dǎo)的課題組在由歐洲心血管學(xué)會主辦的《心血管研究》（Cardiovascular Research）上撰文指出,，一種被命名為miRNA-23a的小核酸可通過調(diào)控靶基因的表達,，進而控制血管內(nèi)皮細(xì)胞的凋亡，并成功揭示了其致病機制,。研究人員稱,，這是國際上首次用小核酸專門針對血管內(nèi)皮細(xì)胞凋亡的系統(tǒng)性研究，有望對心腦血管疾病治療產(chǎn)生積極作用,。
人體血管內(nèi)壁猶如一道天然屏障,，起著重要的免疫防御作用。一旦內(nèi)壁上的內(nèi)皮細(xì)胞死亡,，這道屏障就有被破壞的危險,，直接威脅機體平衡，導(dǎo)致動脈粥樣硬化,、敗血癥休克等頑癥,。如何防治血管內(nèi)皮細(xì)胞凋亡，已成為近十幾年來研究的熱點,。
“這項研究全部得益于國家自然科學(xué)基金的支持,。”研究人員說。據(jù)介紹,，細(xì)胞凋亡不同于細(xì)胞壞死,，是受基因調(diào)節(jié)的一種主動的、程序性的生理過程,。科學(xué)家已經(jīng)獲知,，腫瘤壞死因子TNF-α是迄今發(fā)現(xiàn)的抗腫瘤活性最強的細(xì)胞因子,，在誘導(dǎo)血管內(nèi)皮細(xì)胞凋亡中扮演著關(guān)鍵角色。針對這種誘導(dǎo)介質(zhì),，目前已有一系列抑制凋亡的TNF-α單克隆抗體或溶解性受體問世,。但由于誘導(dǎo)介質(zhì)復(fù)雜，這種單一防治的辦法往往顯得力不從心,，研究者們一直寄希望于能找到一個對內(nèi)皮細(xì)胞凋亡進行總體控制的全新方案,。小核酸miRNA的發(fā)現(xiàn)為深入研究開辟了道路。
中南大學(xué)湘雅二醫(yī)院麻醉科的研究人員利用了小核酸新技術(shù)，并運用于TNF-α介導(dǎo)的細(xì)胞凋亡研究,。他們從860多種已發(fā)現(xiàn)的小核酸中,，經(jīng)過大量比照測試和篩選，將目標(biāo)鎖定為對內(nèi)皮細(xì)胞凋亡影響最明顯的miRNA-23a,。進一步的研究對其在細(xì)胞中的表達進行了成功干預(yù),，結(jié)果發(fā)現(xiàn)：當(dāng)miRNA-23a的表達水平下調(diào)時，靶基因Caspase-7和STK4的表達水平提高了,，從而導(dǎo)致更多的內(nèi)皮細(xì)胞發(fā)生凋亡,。這表明，上調(diào)miRNA-23a的表達水平是抑制內(nèi)皮細(xì)胞凋亡的有效途徑,。
研究人員表示,，miRNA-23a這一新靶點的發(fā)現(xiàn)，對治療諸如動脈硬化等血管性疾病提供了新的思路和方法,，具有較大的潛在臨床價值,。不過miRNA-23a在體內(nèi)很容易降解，下一步研究如能使其穩(wěn)定下來,，其價值將不可估量,。(生物谷Bioon.com)
doi:10.1093/cvr/cvr290
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Effects of down-regulation of microRNA-23a on TNF-α-induced endothelial cell apoptosis through caspase-dependent pathways
Wei Ruan, Jun-mei Xu, Suo-bei Li, Ling-qing Yuan and Ru-ping Dai
Aims: Endothelial cell injury induced by inflammatory factors plays a critical role in the pathogenesis of numerous vascular diseases.microRNAs are well known to be implicated in the cell proliferation and apoptosis in the inflammatory responses. However, it remains to be determined whether microRNAs are associated with tumor necrosis factor (TNF)-α-mediated endothelial cell injury. The aim of the present study is to investigate the role of microRNAs in TNF-α-induced endothelial cell apoptosis. Methods and results: Microarrays were used to analyze the global expression of microRNAs in TNF-α-stimulated human primary endothelial cells. Expression profiles of the microRNAs were verified using qRT-PCR. After TNF-α treatment, twelve miRNAs were dramatically up-regulated and nine were down-regulated. LNA-anti-miR-23a and pre-miR-23a were found to modulate one of the markedly down-regulated miRNAs, miR-23a, which could in turn increase or attenuate TNF-α-induced endothelial cell apoptosis. Bioinformatics analysis suggested that caspase-7 and serine/threonine kinase 4 (STK4) are potential targets of miR-23a. LNA-anti-miR-23a enhanced, but pre-miR-23a inhibited the activation of caspase-7, STK4 and its related signaling caspase-3 after TNF-α treatment. However, pre-miR-23a or LNA-anti-miR-23a had no effect on TNF-α-induced Bcl-2 activation. Conclusion: Our results suggest that miR-23a may be involved in TNF-α-induced endothelial cell apoptosis through regulation of the caspase-7 and STK-4-caspase-3 pathways.
