Postnatal deficiency of ADAMTS1 ameliorates thoracic aortic aneurysm and dissection in mice.
Postnatal deficiency of ADAMTS1 ameliorates thoracic aortic aneurysm and dissection in mice.
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出生后 ADAMTS1 缺陷可改善小鼠胸主动脉瘤和夹层。
DOI：
10.1113/ep087018
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发表时间：
2018
影响因子：
2.7
通讯作者：
Zheng Jingang
中科院分区：
文献类型：
--
作者：
Wang Shanshan;Liu Yuting;Zhao Guizhen;He Li;Fu Yi;Yu Changan;Wang Zhizhi;Zhao Tingting;Cao Fan;Gao Yanxiang;Kong Wei;Zheng Jingang
新发现本研究的中心问题是什么？胸主动脉瘤和夹层（TAAD）的特征是细胞外基质重塑和炎症反应。有证据表明ADAMTS 1与TAAD的发生密切相关，但它是否对TAAD的病理生理学有贡献仍不清楚。主要发现及其重要性是什么？我们建立了可诱导的出生后ADAMTS 1基因敲除小鼠，发现ADAMTS 1缺陷减弱了β-氨基丙腈依赖性TAAD的形成和破裂。ADAMTS 1缺陷可通过抑制炎性细胞因子水平和巨噬细胞迁移，抑制中性粒细胞和巨噬细胞在β-氨基丙腈诱导的TAAD早期的浸润。ADAMTS 1可能成为TAAD治疗的新靶点。具有血小板反应蛋白基序的去整合素和金属蛋白酶1（ADAMTS 1）是一种炎症相关蛋白，能够降解动脉中的细胞外基质蛋白。在此，我们研究了ADAMTS 1是否参与小鼠TAAD的病理生理学。使用β-氨基丙腈（BAPN）诱导的TAAD小鼠模型，我们发现ADAMTS 1表达在TAAD发展的早期阶段开始上调，并主要定位在主动脉外膜。产生ADAMTS 1-floxed小鼠和全身他莫昔芬诱导的ADAMTS 1敲除小鼠（ADAMTS 1 flox/floxUbc-CreERT 2+，ADAMTS 1 KO）来研究ADAMTS 1在TAAD发展中的直接因果作用。ADAMTS 1 KO小鼠BAPN诱导的TAAD发生率和破裂率均显著低于ADAMTS 1flox/plant小鼠（分别为45.5vs81.8%和18.2vs42.4%）。BAPN处理的ADAMTS 1flox/Kappa小鼠主动脉弹性膜严重破坏，外膜中大量中性粒细胞和巨噬细胞聚集，外周血中中性粒细胞比例明显增加，TAAD诱导早期炎性因子表达显著增加，所有这些在ADAMTS 1 KO小鼠中均受到明显抑制。此外，ADAMTS 1缺陷型巨噬细胞在体内和体外均表现出丧失的迁移能力。结论ADAMTS 1通过调节炎症反应在出生后TAAD的形成和破裂过程中发挥重要作用，提示ADAMTS 1可能成为TAAD治疗的新靶点。
New FindingsWhat is the central question of this study?Thoracic aortic aneurysm and dissection (TAAD) is characterized by extracellular matrix remodelling and an inflammatory response. Evidence suggests thatADAMTS1is closely associated with TAAD development, but whether it contributes to the pathophysiology of TAAD remains unknown.What is the main finding and its importance?We generated inducible postnatalADAMTS1knockout mice and found thatADAMTS1deficiency attenuated β‐aminopropionitrile‐dependent TAAD formation and rupture. Furthermore,ADAMTS1deficiency suppressed neutrophil and macrophage infiltration by inhibiting inflammatory cytokine levels and macrophage migration during the early stage of β‐aminopropionitrile‐induced TAAD.ADAMTS1could be a new therapeutic target for TAAD.AbstractThoracic aortic aneurysm and dissection (TAAD), as a life‐threatening cardiovascular disease, is characterized by extracellular matrix remodelling and an inflammatory response. A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) is an inflammation‐related protein that is able to degrade extracellular matrix proteins in arteries. Herein, we investigated whetherADAMTS1contributes to the pathophysiology of TAAD in mice. Using the mouse model of β‐aminopropionitrile (BAPN)‐induced TAAD, we found thatADAMTS1expression was upregulated beginning in the early stage of TAAD development and localized predominantly in the aortic adventitia.ADAMTS1‐floxed mice and whole‐body tamoxifen‐inducibleADAMTS1knockout mice (ADAMTS1flox/floxUbc‐CreERT2+,ADAMTS1KO) were generated to investigate the direct causal role ofADAMTS1in TAAD development. The incidence and rupture rates of BAPN‐induced TAAD inADAMTS1KO mice were significantly lower than those inADAMTS1flox/floxmice (45.5versus81.8% and 18.2versus42.4%, respectively). Aortas from BAPN‐treatedADAMTS1flox/floxmice displayed profound destruction of the elastic lamellae, abundant neutrophil and macrophage accumulation in the adventitia, obviously increased neutrophil proportions in peripheral blood and significantly increased expression of inflammatory factors in the early stage of TAAD induction, all of which were markedly suppressed inADAMTS1KO mice. Furthermore,ADAMTS1‐deficient macrophages exhibited abrogated migration capacity bothin vivoandin vitro. In conclusion,ADAMTS1plays a crucial role in postnatal TAAD formation and rupture by regulating inflammatory responses, suggesting thatADAMTS1might be a new therapeutic target for TAAD.