Intraplatelet miRNA-126 regulates thrombosis and its reduction contributes to platelet inhibition.

IF 10.2 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Research Pub Date : 2024-11-05 DOI:10.1093/cvr/cvae138
Lu-Jun Zhang, Yang-Xi Hu, Rong-Zhong Huang, Yan-Yan Xu, Shao-Hua Dong, Fang-Hao Guo, Jun-Jun Guo, Jing-Jing Qiu, Zi-Yun Cao, Li-Jiang Wei, Jia-Hao Mao, Ankang Lyu, Jun-Ling Liu, Xian-Xian Zhao, Zhi-Fu Guo, Qing Jing
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Abstract

Aims: MicroRNA-126 (miR-126), one of the most abundant microRNAs in platelets, is involved in the regulation of platelet activity and the circulating miR-126 is reduced during antiplatelet therapy. However, whether intraplatelet miR-126 plays a role in thrombosis and platelet inhibition remains unclear.

Methods and results: Here, using tissue-specific knockout mice, we reported that the deficiency of miR-126 in platelets and vascular endothelial cells significantly prevented thrombosis and prolonged bleeding time. Using chimeric mice, we identified that the lack of intraplatelet miR-126 significantly prevented thrombosis. Ex vivo experiments further demonstrated that miR-126-deficient platelets displayed impaired platelet aggregation, spreading, and secretory functions. Next, miR-126 was confirmed to target phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) in platelet, which encodes a negative regulator of the phosphoinositide 3-kinase/protein kinase B pathway, enhancing platelet activation through activating the integrin αIIbβ3-mediated outside-in signalling. After undergoing myocardial infarction (MI), chimeric mice lacking intraplatelet miR-126 displayed reduced microvascular obstruction and prevented MI expansion in vivo. In contrast, overexpression of miR-126 by the administration of miR-126 agonist (agomiR-126) in wild-type mice aggravated microvascular obstruction and promoted MI expansion, which can be almost abolished by aspirin administration. In patients with cardiovascular diseases, antiplatelet therapies, either aspirin alone or combined with clopidogrel, decreased the level of intraplatelet miR-126. The reduction of intraplatelet miR-126 level was associated with the decrease in platelet activity.

Conclusion: Our murine and human data reveal that (i) intraplatelet miR-126 contributes to platelet activity and promotes thrombus formation, and (ii) the reduction of intraplatelet miR-126 contributes to platelet inhibition during antiplatelet therapy.

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血小板内 miRNA-126 调节血栓形成,其减少有助于抑制血小板。
目的:MicroRNA-126(miR-126)是血小板中最丰富的微RNA之一,参与血小板活性的调控,在抗血小板治疗期间,循环中的miR-126会减少。然而,血小板内 miR-126 是否在血栓形成和血小板抑制中发挥作用仍不清楚:在此,我们利用组织特异性基因敲除小鼠报道了血小板和血管内皮细胞中 miR-126 的缺乏能显著预防血栓形成和延长出血时间。通过嵌合小鼠,我们发现血小板内 miR-126 的缺乏能明显预防血栓形成。体内外实验进一步证明,缺失 miR-126 的血小板显示出血小板聚集、扩散和分泌功能受损。接下来,miR-126 被证实靶向血小板中的磷酸肌醇-3 激酶调节亚基 2(PIK3R2),该亚基编码 PI3 K/AKT 通路的负调控因子,通过激活整合素 αⅡbβ3 介导的外入信号增强血小板活化。缺失血小板内 miR-126 的嵌合小鼠在经历心肌梗死(MI)后,微血管阻塞减少,并能防止 MI 在体内扩大。相反,在野生型小鼠体内通过施用 miR-126 激动剂(agomiR-126)过表达 miR-126,会加重微血管阻塞并促进心肌梗死扩大,而施用阿司匹林几乎可以消除这种情况。在心血管疾病患者中,抗血小板疗法,无论是单独使用阿司匹林还是与氯吡格雷联合使用,都会降低血小板内 miR-126 的水平。血小板内 miR-126 水平的降低与血小板活性的降低有关:我们的小鼠和人体数据显示:(i) 血小板内 miR-126 有助于血小板活性并促进血栓形成;(ii) 在抗血小板治疗期间,血小板内 miR-126 的减少有助于抑制血小板。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cardiovascular Research
Cardiovascular Research 医学-心血管系统
CiteScore
21.50
自引率
3.70%
发文量
547
审稿时长
1 months
期刊介绍: Cardiovascular Research Journal Overview: International journal of the European Society of Cardiology Focuses on basic and translational research in cardiology and cardiovascular biology Aims to enhance insight into cardiovascular disease mechanisms and innovation prospects Submission Criteria: Welcomes papers covering molecular, sub-cellular, cellular, organ, and organism levels Accepts clinical proof-of-concept and translational studies Manuscripts expected to provide significant contribution to cardiovascular biology and diseases
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