Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling.
Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling.
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DOI：
10.1161/atvbaha.117.310562
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Mayr M
中科院分区：
文献类型：
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作者：
Fava M;Barallobre-Barreiro J;Mayr U;Lu R;Didangelos A;Baig F;Lynch M;Catibog N;Joshi A;Barwari T;Yin X;Jahangiri M;Mayr M
文本中提供了补充数字内容。胸主动脉瘤（TAA）是一种主动脉壁退行性疾病，伴随着主动脉ECM（细胞外基质）结构和成分的变化。 ADAMTS（一种具有血小板反应蛋白基序的解整合素和金属蛋白酶）蛋白酶家族最近与 TAA 形成有关。本研究旨在探讨 ADAMTS-5 对 TAA 发展的贡献。在缺乏 ADAMTS-5 (Adamts5Δcat) 催化结构域的小鼠中采用 AngII（血管紧张素 II）输注建立主动脉扩张模型。 Adamts5Δcat 小鼠血压升高减弱，同时升主动脉 (AsAo) 扩张增加。有趣的是，对 AngII 处理的野生型小鼠和 Adamts5Δcat 小鼠的主动脉 ECM 进行蛋白质组比较，结果显示多功能蛋白聚糖是 Adamts5Δcat 小鼠中上调最多的 ECM 蛋白。伴随着 ADAMTS 特异性多功能蛋白聚糖裂解产物 (versikine) 的显着减少和 LRP1（低密度脂蛋白相关蛋白 1）的减少。沉默人主动脉平滑肌细胞中 LRP1 的表达会降低 ADAMTS5 的表达，减弱 versikine 的产生，但会增加可溶性 ADAMTS-1。在 AngII 处理的 Adamts5Δcat 小鼠的主动脉中观察到 ADAMTS-1 的类似增加，但不足以维持多功能蛋白处理并防止主动脉扩张。我们的结果支持 ADAMTS 蛋白酶在 TAA 中的新兴作用。 ADAMTS-5 而不是 ADAMTS-1 是小鼠主动脉中多功能蛋白聚糖调节的关键蛋白酶。需要进一步研究来确定不同 ADAMTS 蛋白酶的 ECM 底物及其对 TAA 形成的贡献。
Supplemental Digital Content is available in the text. Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic ECM (extracellular matrix). The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteases has recently been implicated in TAA formation. This study aimed to investigate the contribution of ADAMTS-5 to TAA development. A model of aortic dilatation by AngII (angiotensin II) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5Δcat). Adamts5Δcat mice showed an attenuated rise in blood pressure while displaying increased dilatation of the ascending aorta (AsAo). Interestingly, a proteomic comparison of the aortic ECM from AngII-treated wild-type and Adamts5Δcat mice revealed versican as the most upregulated ECM protein in Adamts5Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of LRP1 (low-density lipoprotein-related protein 1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5, attenuated the generation of versikine, but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Δcat mice but was not sufficient to maintain versican processing and prevent aortic dilatation. Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Further studies are needed to define the ECM substrates of the different ADAMTS proteases and their contribution to TAA formation.