The Nonproteolytic Intracellular Domain of Membrane-Type 1 Matrix Metalloproteinase Coordinately Modulates Abdominal Aortic Aneurysm and Atherosclerosis in Mice-Brief Report.
The Nonproteolytic Intracellular Domain of Membrane-Type 1 Matrix Metalloproteinase Coordinately Modulates Abdominal Aortic Aneurysm and Atherosclerosis in Mice-Brief Report.
复制标题
膜型1基质金属蛋白酶的非蛋白质解体内结构域协同调节腹主动脉瘤和动脉粥样硬化报告中。
DOI：
10.1161/atvbaha.122.317686
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发表时间：
2022-10
影响因子：
8.7
通讯作者：
Ramkhelawon, Bhama
中科院分区：
文献类型：
--
作者：
Silvestro, Michele;Rivera, Cristobal F.;Alebrahim, Dornazsadat;Vlahos, John;Pratama, Muhammad Yogi;Lu, Cuijie;Tang, Claudia;Harpel, Zander;Tellaoui, Rayan Sleiman;Zias, Ariadne L.;Maldonado, Delphina J.;Byrd, Devon;Attur, Mukundan;Mignatti, Paolo;Ramkhelawon, Bhama
关键词：
MT 1-MMP（membrane-type 1 matrix metalloproteinase，MMP-14）是一种跨膜锚定蛋白，具有细胞外蛋白酶结构域和缺乏蛋白水解功能的胞质尾区，但能够介导调节组织稳态的细胞内信号传导。MT 1-MMP细胞外蛋白水解活性已显示调节主动脉瘤和动脉粥样硬化的病理性重构。然而，MT 1-MMP的非蛋白水解胞内结构域在腹主动脉瘤（AAA）血管重塑中的作用尚不清楚。我们产生了一个突变的小鼠，窝藏在MT 1-MMP胞质结构域的点突变（Y 573 D），废除MT 1-MMP信号转导功能，而不影响其蛋白水解活性。对这些小鼠及其对照野生型同窝小鼠进行实验性AAA，通过血管紧张素II输注结合PCSK 9（前蛋白转化酶枯草杆菌蛋白酶/kexin 9型）过表达和高胆固醇喂养进行建模。突变小鼠比对照小鼠发生更严重的AAA，伴随着动脉瘤内动脉粥样硬化病变的产生，巨噬细胞浸润和弹性蛋白降解显著增加。来自突变小鼠的主动脉病变相关的和骨髓来源的巨噬细胞表现出增强的炎症状态，并表达了升高水平的促炎性Netrin-1，这是一种先前证明可促进动脉粥样硬化和AAA的蛋白质。我们的研究结果表明，MT 1-MMP的胞质结构域通过与Netrin-1表达相关的蛋白水解无关的信号传导机制来保护AAA和动脉粥样硬化斑块的发展。MT 1-MMP的这种意想不到的功能揭示了AAA和动脉粥样硬化形成同步发生的新机制，并突出了其在控制血管壁稳态中的重要性。本文提供了一个图形摘要。
MT1-MMP (membrane-type 1 matrix metalloproteinase, MMP-14) is a transmembrane-anchored protein with an extracellular proteinase domain and a cytoplasmic tail devoid of proteolytic functions but capable of mediating intracellular signaling that regulates tissue homeostasis. MT1-MMP extracellular proteolytic activity has been shown to regulate pathological remodeling in aortic aneurysm and atherosclerosis. However, the role of the nonproteolytic intracellular domain of MT1-MMP in vascular remodeling in abdominal aortic aneurysms (AAA) is unknown. We generated a mutant mouse that harbors a point mutation (Y573D) in the MT1-MMP cytoplasmic domain that abrogates the MT1-MMP signaling function without affecting its proteolytic activity. These mice and their control wild-type littermates were subjected to experimental AAA modeled by angiotensin II infusion combined with PCSK9 (proprotein convertase subtilisin/kexin type 9) overexpression and high-cholesterol feeding. The mutant mice developed more severe AAA than the control mice, with concomitant generation of intraaneurysmal atherosclerotic lesions and dramatically increased macrophage infiltration and elastin degradation. Aortic lesion-associated and bone marrow–derived macrophages from the mutant mice exhibited an enhanced inflammatory state and expressed elevated levels of proinflammatory Netrin-1, a protein previously demonstrated to promote both atherosclerosis and AAA. Our findings show that the cytoplasmic domain of MT1-MMP safeguards from AAA and atherosclerotic plaque development through a proteolysis-independent signaling mechanism associated with Netrin-1 expression. This unexpected function of MT1-MMP unveils a novel mechanism of synchronous onset of AAA and atherogenesis and highlights its importance in the control of vascular wall homeostasis. A graphic abstract is available for this article.