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The expression and localization of membrane type-1 matrix metalloproteinase in human abdominal aortic aneurysms
A Nollendorfs1, T C Greiner, H Nagase
1Department of Surgery, University of Nebraska Medical Center, Omaha 68198-7690, USA.
Background And Objective:
Matrix metalloproteinase-2 (MMP-2) degrades both fibrillar collagens and elastin. MMP-2 is secreted as a latent 72-kd proenzyme that must be proteolytically processed to the 62-kd active form. In our laboratory we demonstrated a significant increase of active, matrix-bound MMP-2 in abdominal aortic aneurysmal (AAA) tissue compared with nonaneurysmal aorta with arteriosclerotic occlusive disease and normal aortic tissue. This increase in active MMP-2 is considered to be important in aneurysm pathogenesis, but the mechanism of its activation in aortic tissue is unknown. Membrane type-1 MMP (MT-1 MMP) is known to be an activator of MMP-2. The purpose of this study was to determine MT-1 MMP expression and its involvement in pro-MMP-2 activation in human aneurysmal tissue.
Methods:
Infrarenal aortic tissue was obtained during the surgical repair of AAAs or the bypass of aortoiliac occlusive disease, or from nondiseased aorta, and the expression of MT-1 MMP messenger RNA was determined with Northern blot analysis. MT-1 MMP protein was determined with immunoblot and immunohistochemistry. The ability of aortic tissue to activate pro-MMP-2 was analyzed by incubating aortic tissue with exogenous radiolabeled pro-MMP-2.
Results:
MT-1 MMP messenger RNA and protein are increased in AAA (P <.05) compared with arteriosclerotic occlusive disease and normal aortic tissue. Immunohistochemical analysis localized MT-1 MMP to aortic smooth muscle cells and macrophages in aneurysmal tissue. AAA tissue demonstrated a greater capacity to activate exogenous pro-MMP-2 compared with atherosclerotic and normal aortic tissue (P <.05).
Conclusion:
These studies demonstrate that MT-1 MMP is increased in AAA tissue and suggest that it may be important in AAA pathogenesis through its ability to activate pro-MMP-2
Insights
Matrix metalloproteinase-2 (MMP-2) activation in abdominal aortic aneurysms (AAA) is increased due to higher levels of its activator, membrane type-1 MMP (MT-1 MMP). This suggests MT-1 MMP plays a key role in AAA development.
Area of Science:
- Cardiovascular Biology
- Enzymology
- Atherosclerosis Research
Background:
- Matrix metalloproteinase-2 (MMP-2) degrades extracellular matrix components like collagen and elastin.
- Active MMP-2 is elevated in abdominal aortic aneurysm (AAA) tissue, suggesting a role in pathogenesis.
- The mechanism of MMP-2 activation within aortic tissue remains unclear.
Purpose of the Study:
- To investigate the expression of membrane type-1 MMP (MT-1 MMP) in human AAA tissue.
- To determine the role of MT-1 MMP in the activation of pro-MMP-2 in AAA.
Main Methods:
- Analysis of MT-1 MMP messenger RNA and protein levels in AAA, arteriosclerotic occlusive disease, and normal aortic tissues.
- Immunohistochemical localization of MT-1 MMP in aneurysmal tissue.
- Assay of pro-MMP-2 activation capacity in aortic tissue samples.
Main Results:
- MT-1 MMP messenger RNA and protein expression were significantly increased in AAA tissue compared to controls.
- Immunohistochemistry revealed MT-1 MMP localized to smooth muscle cells and macrophages in AAA.
- AAA tissue exhibited a significantly enhanced ability to activate pro-MMP-2.
Conclusions:
- MT-1 MMP expression is upregulated in human AAA tissue.
- Increased MT-1 MMP in AAA likely contributes to aneurysm pathogenesis by activating pro-MMP-2.