MMP17/MT4-MMP and thoracic aortic aneurysms: OPNing new potential for effective treatment.
MMP17/MT4-MMP and thoracic aortic aneurysms: OPNing new potential for effective treatment.
复制标题
MMP17/MT4-MMP 和胸主动脉瘤：OPNing 有效治疗的新潜力。
DOI：
10.1161/circresaha.117.306851
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发表时间：
2015
影响因子：
20.1
通讯作者：
Yanagisawa,Hiromi
中科院分区：
文献类型：
--
作者：
Papke,ChristinaL;Yamashiro,Yoshito;Yanagisawa,Hiromi
110 Circulation Research July 3, 2015 osteopontin can also act on MMPs by enhancing the activity of pro-MMP927. Furthermore, osteopontin has been found to be increased in some instances of TAA. 15 However, much still remains unknown about specific functions of osteopontin in the aortic wall, and its role in aneurysm formation, including the degree to which it is cleaved in the aortic wall. In this issue of Circulation Research, Martin-Alonso et al28 reported a missense mutation in MMP17 gene (p. Arg373His) as the possible causal mutation for acute ascending aortic aneurysms using whole-exome sequencing. The R373H mutation was predicted to cause a conformational change in the C-terminal region that hinders the binding of the glycosylphosphatidylinositol (GPI)-tail to the endoplasmic reticulum and form an energy unstable heterodimer with wild-type MMP17. Indeed, the authors showed compromised expression of R373H protein in transfected cells, suggesting a functional homozygous loss, which is surprising considering the well-known functions of MMPs as matrix degrading enzymes and the increased expression reported in aortic aneurysms in mice and humans. 29, 30The authors then turned into a mouse model (Mmp17−/−) to investigate the impact of loss of MMP17 in the aortic development and aneurysm formation. Although these mice showed a marginal increase in aortic lumen diameter, no spontaneous aneurysm or dissection was observed. However, when challenged with chronic infusion of angiotensin II or carotid artery ligation, the mutants exhibited higher incidence of TAA (but not AAA) and developed more prominent neointimas, respectively, suggesting an altered response to pathological stimuli and dysfunctional SMCs. Ultrastructural analyses revealed various morphological abnormalities in the Mmp17−/− aorta, including radially oriented SMCs with round cell shape, disconnection of SMCs from elastin lamelli, an increase in collagen fibers, altered distribution of SMC marker proteins, and a transient increase in proliferating SMCs, affecting the maturation of SMCs (Figure).
