期刊
JOURNAL OF SURGICAL RESEARCH
卷 183, 期 1, 页码 472-477出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jss.2012.12.012
关键词
Thoracic aortic aneurysm; Angiotensin II; Transforming growth factor beta; Smad2; Matrix metalloproteinase-9; Extracellular signal-regulated kinase
类别
资金
- Japan Society for the Promotion of Science
- Takeda Science Foundation
- SENSHIN Medical Research Foundation
- Grants-in-Aid for Scientific Research [22659232, 22591543] Funding Source: KAKEN
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.
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