Gong Ze, Huang Jiaqi, Wang Daidai, Yang Shiyu, Ma Zihan, Fu Yi, Ma Qingbian, Kong Wei
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China.
Department of Emergency Medicine, Peking University Third Hospital, Beijing, 100191, People's Republic of China.
J Mol Med (Berl). 2023 Mar;101(3):237-248. doi: 10.1007/s00109-023-02284-w. Epub 2023 Jan 20.
Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular disease with severe extracellular matrix (ECM) remodeling that lacks efficient early stage diagnosis and nonsurgical therapy. A disintegrin and metalloproteinase with thrombospondin motif 7 (ADAMTS-7) is recognized as a novel locus for human coronary artery atherosclerosis. Previous work by us and others showed that ADAMTS-7 promoted atherosclerosis, postinjury neointima formation, and vascular calcification. However, whether ADAMTS-7 is involved in TAAD pathogenesis is unknown. We aimed to explore the alterations in ADAMTS-7 expression in human and mouse TAAD, and investigate the role of ADAMTS-7 in TAAD formation. A case-control study of TAAD patients (N = 86) and healthy participants (N = 88) was performed. The plasma ADAMTS-7 levels were markedly increased in TAAD patients within 24 h and peaked in 7 days. A TAAD mouse model was induced with 0.5% β-aminopropionitrile (BAPN) in drinking water. ELISA analysis of mouse plasma, Western blotting, and immunohistochemical staining of aorta showed an increase in ADAMTS-7 in the early stage of TAAD. Moreover, ADAMTS-7-deficient mice exhibited significantly attenuated TAAD formation and TAAD rupture-related mortality in both male and female mice, which was accompanied by reduced artery dilation and inhibited elastin degradation. ADAMTS-7 deficiency caused repressed inflammatory response and complement system activation during TAAD formation. An increase in plasma ADAMTS-7 is a novel biomarker for human TAAD. ADAMTS-7 deficiency attenuates BAPN-induced murine TAAD. ADAMTS-7 is a potential novel target for TAAD diagnosis and therapy. KEY MESSAGES: A case-control study revealed increased plasma ADAMTS-7 is a risk factor for TAAD. ADAMTS-7 was elevated in plasma and aorta at early stage of mouse TAAD. ADAMTS-7 knockout attenuated mouse TAAD formation and mortality in both sexes.
胸主动脉瘤和夹层（TAAD）是一种危及生命的心血管疾病，伴有严重的细胞外基质（ECM）重塑，缺乏有效的早期诊断和非手术治疗方法。含血小板反应蛋白基序的解聚素和金属蛋白酶7（ADAMTS-7）被认为是人类冠状动脉粥样硬化的一个新位点。我们和其他人之前的研究表明，ADAMTS-7促进动脉粥样硬化、损伤后内膜增生和血管钙化。然而，ADAMTS-7是否参与TAAD发病机制尚不清楚。我们旨在探讨ADAMTS-7在人和小鼠TAAD中的表达变化，并研究ADAMTS-7在TAAD形成中的作用。对TAAD患者（N = 86）和健康参与者（N = 88）进行了病例对照研究。TAAD患者血浆ADAMTS-7水平在24小时内显著升高，并在7天达到峰值。用0.5%β-氨基丙腈（BAPN）诱导建立TAAD小鼠模型。对小鼠血浆进行ELISA分析、蛋白质免疫印迹以及对主动脉进行免疫组织化学染色，结果显示TAAD早期ADAMTS-7增加。此外，ADAMTS-7缺陷小鼠的TAAD形成和TAAD破裂相关死亡率在雄性和雌性小鼠中均显著降低，同时伴有动脉扩张减轻和弹性蛋白降解受抑制。ADAMTS-7缺陷导致TAAD形成过程中炎症反应和补体系统激活受到抑制。血浆ADAMTS-7升高是人类TAAD的一种新型生物标志物。ADAMTS-7缺陷减轻了BAPN诱导的小鼠TAAD。ADAMTS-7是TAAD诊断和治疗的潜在新靶点。关键信息：病例对照研究表明，血浆ADAMTS-7升高是TAAD的一个危险因素。在小鼠TAAD早期，血浆和主动脉中的ADAMTS-7升高。ADAMTS-7基因敲除减轻了小鼠TAAD的形成和两性死亡率。
