近日，中南大学麻醉医学研究所教授徐军美领导的课题组在由欧洲心血管学会主办的《心血管研究》（Cardiovascular Research）上撰文指出，一种被命名为miRNA-23a的小核酸可通过调控靶基因的表达，进而控制血管内皮细胞的凋亡，并成功揭示了其致病机制。研究人员称，这是国际上首次用小核酸专门针对血管内皮细胞凋亡的系统性研究，有望对心脑血管疾病治疗产生积极作用。
人体血管内壁犹如一道天然屏障，起着重要的免疫防御作用。一旦内壁上的内皮细胞死亡，这道屏障就有被破坏的危险，直接威胁机体平衡，导致动脉粥样硬化、败血症休克等顽症。如何防治血管内皮细胞凋亡，已成为近十几年来研究的热点。
“这项研究全部得益于国家自然科学基金的支持。”研究人员说。据介绍，细胞凋亡不同于细胞坏死，是受基因调节的一种主动的、程序性的生理过程。科学家已经获知，肿瘤坏死因子TNF-α是迄今发现的抗肿瘤活性最强的细胞因子，在诱导血管内皮细胞凋亡中扮演着关键角色。针对这种诱导介质，目前已有一系列抑制凋亡的TNF-α单克隆抗体或溶解性受体问世。但由于诱导介质复杂，这种单一防治的办法往往显得力不从心，研究者们一直寄希望于能找到一个对内皮细胞凋亡进行总体控制的全新方案。小核酸miRNA的发现为深入研究开辟了道路。
中南大学湘雅二医院麻醉科的研究人员利用了小核酸新技术，并运用于TNF-α介导的细胞凋亡研究。他们从860多种已发现的小核酸中，经过大量比照测试和筛选，将目标锁定为对内皮细胞凋亡影响最明显的miRNA-23a。进一步的研究对其在细胞中的表达进行了成功干预，结果发现：当miRNA-23a的表达水平下调时，靶基因Caspase-7和STK4的表达水平提高了，从而导致更多的内皮细胞发生凋亡。这表明，上调miRNA-23a的表达水平是抑制内皮细胞凋亡的有效途径。
研究人员表示，miRNA-23a这一新靶点的发现，对治疗诸如动脉硬化等血管性疾病提供了新的思路和方法，具有较大的潜在临床价值。不过miRNA-23a在体内很容易降解，下一步研究如能使其稳定下来，其价值将不可估量。(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.
