Deficiency of MMP17/MT4-MMP Proteolytic Activity Predisposes to Aortic Aneurysm in Mice
Deficiency of MMP17/MT4-MMP Proteolytic Activity Predisposes to Aortic Aneurysm in Mice
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DOI：
10.1161/circresaha.117.305108
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发表时间：
2015-07-03
影响因子：
20.1
通讯作者：
Arroyo, Alicia G.
中科院分区：
文献类型：
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作者：
Martin-Alonso, Mara;Garcia-Redondo, Ana B.;Arroyo, Alicia G.
理论基础：在发达国家，由动脉瘤引起的主动脉夹层或破裂导致1%至2%的死亡。这些疾病与影响血管平滑肌细胞分化和收缩或细胞外基质组成和组装的基因突变有关。目的：探讨MMP17/MT4-MMP1在动脉壁中的作用及其在人类主动脉病变中的可能作用。方法和结果：对遗传性胸主动脉瘤和夹层患者进行筛查，发现MMP17基因中的一个错义突变(R373H)阻止了该酶在人类转基因细胞中的表达。利用功能丧失的遗传小鼠模型，我们证明了Mmp17的缺失导致血管平滑肌细胞功能障碍和血管壁细胞外基质的改变，并导致对血管紧张素-II诱导的胸主动脉瘤的易感性增加。我们还发现，在主动脉壁发育过程中，Mmp17介导的骨桥蛋白通过c-jun氨基末端激酶信号调节血管平滑肌细胞的成熟。在Mmp17缺失的新生儿中，催化活性的Mmp17或骨桥蛋白N末端片段的重新表达可以阻止动脉表型的某些特征。结论：Mmp17的蛋白分解活性调节动脉血管壁血管平滑肌细胞的表型，其缺失易导致小鼠胸主动脉瘤的发生。通过慢病毒策略挽救部分血管壁表型，为这些危及生命的疾病的治疗干预开辟了途径。
Rationale: Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries. These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome.Objective: To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology.Methods and Results: Screening of patients with inherited thoracic aortic aneurysms and dissections identified a missense mutation (R373H) in the MMP17 gene that prevented the expression of the protease in human transfected cells. Using a loss-of-function genetic mouse model, we demonstrated that the lack of Mmp17 resulted in the presence of dysfunctional vascular smooth muscle cells and altered extracellular matrix in the vessel wall; and it led to increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. We also showed that Mmp17-mediated osteopontin cleavage regulated vascular smooth muscle cell maturation via c-Jun N-terminal kinase signaling during aorta wall development. Some features of the arterial phenotype were prevented by re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment in Mmp17-null neonates.Conclusions: Mmp17 proteolytic activity regulates vascular smooth muscle cell phenotype in the arterial vessel wall, and its absence predisposes to thoracic aortic aneurysm in mice. The rescue of part of the vessel-wall phenotype by a lentiviral strategy opens avenues for therapeutic intervention in these life-threatening disorders.