Important role of the angiotensin II pathway in producing matrix metalloproteinase-9 in human thoracic aortic aneurysms
Important role of the angiotensin II pathway in producing matrix metalloproteinase-9 in human thoracic aortic aneurysms
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DOI：
10.1016/j.jss.2012.12.012
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发表时间：
2013-07-01
影响因子：
2.2
通讯作者：
Hamano, Kimikazu
中科院分区：
文献类型：
--
作者：
Nagasawa, Ayako;Yoshimura, Koichi;Hamano, Kimikazu
背景：除了基质金属蛋白酶-9 （MMP-9）被认为是降解动脉瘤壁细胞外基质的关键酶外，人类胸主动脉瘤（TAAs）的确切病理机制尚不清楚。本研究的目的是阐明血管紧张素II （AngII）途径对人TAA壁MMP-9产生的意义。方法和结果：我们检测了Smad2 （AngII和转化生长因子β (tgf - β)途径的常见下游分子）的激活以及MMP-9在人非综合征TAA壁中的表达。我们观察到Smad2激活和MMP-9表达的显著增加，这与弹性薄片的破坏有关。利用体外培养的人TAA壁，我们研究了AngII和/或tgf - β通路是否对MMP-9的产生至关重要。出乎意料的是，tgf - β受体抑制剂对MMP-9的产生没有影响。我们使用了细胞外信号调节激酶（ERK）激活抑制剂PD98059，并证明PD98059显著降低了MMP-9的产生，并减弱了Smad2的激活。此外，外源性AngII以erk依赖的方式导致Smad2激活和MMP-9产生的增加。结论：我们的研究结果表明，AngII/ERK通路在人非综合征TAA壁MMP-9的产生中起重要作用。(C) 2013爱思唯尔公司版权所有。
Background: The precise pathologic mechanisms underlying human thoracic aortic aneurysms (TAAs) remain uncertain, except that matrix metalloproteinase-9 (MMP-9) is considered a key enzyme for the degradation of extracellular matrix in aneurysm walls. The aim of this study was to elucidate the significance of the angiotensin II (AngII) pathway to MMP-9 production in human TAA walls.Methods and results: We examined the activation of Smad2, a common downstream molecule of AngII and transforming growth factor beta (TGF-beta) pathways, and the expression of MMP-9 in human nonsyndromic TAA walls. We observed significant increases in Smad2 activation and MMP-9 expression, associated with disruption of elastic lamellae. Using human TAA walls in ex vivo culture, we investigated whether AngII and/or TGF-beta pathways are essential for MMP-9 production. Unexpectedly, TGF-beta receptor inhibitor had no effect on MMP-9 production. We used PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) activation, and demonstrated that PD98059 dramatically reduced MMP-9 production with attenuation of Smad2 activation. Moreover, exogenous AngII resulted in increases in Smad2 activation and MMP-9 production, in an ERK-dependent manner.Conclusion: Our findings indicate that the AngII/ERK pathway has an important role in the production of MMP-9 in human nonsyndromic TAA walls. (C) 2013 Elsevier Inc. All rights reserved.