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Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms
Borhane Annabi1, Daniel Shédid, Pierre Ghosn
1Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, Hôpital Sainte-Justine-UQAM, Montreal, PQ, Canada.
Background:
The increased synthesis of matrix metalloproteinases (MMPs) by aortic smooth muscle cells (SMCs) is thought to be involved in the etiopathogenesis of abdominal aortic aneurysms (AAAs), but the functional regulation and the activation states of these MMPs remain unclear. In this study, we assessed the expression levels and the functional regulation of several MMPs in the pathogenesis of AAAs.
Methods:
Human healthy aorta and AAA specimens were homogenized, and the proteolytic activities of MMP-2 and MMP-9 and of the macrophage metalloelastase (MMP-12) were assessed with zymography. Protein expression of MMP-1, MMP-12, membrane-type 1 MMP (MT1-MMP), tissue inhibitor of MMP 1 (TIMP-1), TIMP-2, TIMP-3, alpha-actin, and beta-actin was analyzed with electrophoresis on sodium dodecyl sulfate gels and immunoblotting.
Results:
MMP-1, MMP-9, and MMP-12 zymogen levels and proteolytic activities were increased in AAAs when compared with healthy aorta. A severe reduction in alpha-actin--positive vascular SMCs was observed in all the AAA specimens and was correlated with an increase in TIMP-3 but not TIMP-1 or TIMP-2 potential activities. Although pro--MMP-2 activity was decreased, the extent of activated MMP-2 remained unaffected in the AAAs. In accordance with this result, a highly activated MT1-MMP form was also observed in AAAs.
Conclusion:
These data suggest that chronic aortic wall inflammation is mediated by macrophage infiltration, which may account for the destruction of medial elastin, as reflected by SMC down regulation, through increased levels of active MMP-1 and MMP-12. Moreover, altered MT1-MMP proteolytic turnover and differential regulation of TIMP expression in AAAs suggest that tight regulatory mechanisms are involved in the molecular regulation of MMP activation processes in the pathogenesis of AAAs.
Insights
Matrix metalloproteinases (MMPs) are upregulated in abdominal aortic aneurysms (AAAs), contributing to aortic wall inflammation and elastin destruction. Specific MMPs and their inhibitors show altered activity, indicating complex regulatory mechanisms in AAA pathogenesis.
Area of Science:
- Vascular Biology
- Atherosclerosis Research
- Matrix Biology
Background:
- Increased matrix metalloproteinases (MMPs) synthesis by aortic smooth muscle cells (SMCs) is implicated in abdominal aortic aneurysm (AAA) pathogenesis.
- The precise functional regulation and activation states of MMPs in AAAs remain incompletely understood.
Purpose of the Study:
- To assess the expression levels and functional regulation of various MMPs in the pathogenesis of AAAs.
- To investigate the role of MMPs and their inhibitors in the cellular and molecular changes observed in AAA tissue.
Main Methods:
- Zymography was used to assess the proteolytic activities of MMP-2, MMP-9, and MMP-12 in human healthy aorta and AAA specimens.
- Protein expression of MMP-1, MMP-12, MT1-MMP, TIMP-1, TIMP-2, TIMP-3, alpha-actin, and beta-actin was analyzed using SDS-PAGE and immunoblotting.
Main Results:
- Elevated MMP-1, MMP-9, and MMP-12 levels and activities were observed in AAAs compared to healthy aortas.
- A significant reduction in alpha-actin-positive SMCs correlated with increased TIMP-3, while MMP-2 activity was decreased but its activated form remained unchanged.
- Activated MT1-MMP was detected in AAAs, suggesting its role in MMP regulation.
Conclusions:
- Chronic aortic inflammation in AAAs, driven by macrophage infiltration, leads to medial elastin destruction via increased active MMP-1 and MMP-12.
- Altered MT1-MMP turnover and differential TIMP regulation highlight complex molecular mechanisms governing MMP activation in AAA pathogenesis.