Expression of Matrix Metalloproteinases and Their Endogenous Inhibitors in Human Abdominal Aortic Aneurysms

ABSTRACT

PURPOSE: Among the theories in the pathogenesis of abdominal aortic aneurysms, matrix metalloproteinase (MMP)- induced excessive degradation of extracellular matrix protein has been widely recognized. Normally, MMPs keep a balance with their endogenous tissue inhibitors of metalloproteinases (TIMPs). Recently, the MMP-TIMP imbalance has been investigated for potential etiological role in AAA formation. The aim of this study was to define the role of the imbalance between the expressions of the specific MMPs and their physiologic inhibitors (TIMPs) in the formation of human abdominal aortic aneurysm (AAA). METHODS: Aortic tissues from 12 patients with AAAs, 4 age-matched patients with aortoiliac occlusive diseases (AODs), and 6 cadaveric organ donors, as normal controls, were obtained and prepared. The productions and expressions of MMP-2, 9, MT1-MMP and TIMP-1, 2, and 4 were analyzed using gelatin zymography, Western blotting, and immunohistochemistry. RESULTS: In the gelatin zymography, the net matrix-degrading activities were higher in the AAAs and AODs than in the normal control group due to the higher presence of MMP-2 and 9. From the Western blot analysis and immunohistochemistry, those with AAAs and AODs showed significantly higher expressions of MMP-2, 9, and MT1-MMP than the normal control group. However, no differences in the TIMP-1 and 2 expressions were found between the all groups. In contrast, TIMP-4 protein was expressed at a significantly lower level in the AAAs and AODs than in the normal control group. MMP-9/TIMP-1, MMP-2/TIMP-2, and MMP-2/TIMP-4 were significantly different between AAAs and normal control group. From the densitometric analysis of the Western blotting, no significant differences were found in tissue expressions of MMPs and TIMPs between the AAAs and AODs groups, but, in the immunohistochemistry, the AAAs group showed a different distribution of the MMP expression confined to sites of overt medial damage compared with that in the intimal plaque in AODs. CONCLUSION: The imbalance of expression between specific MMPs and their endogenous inhibitors plays an etiological role in the formation of AAAs. In addition, TIMP-4 may suppress the MMP-induced aneurysmal formation. Our results suggest that the eventual formation of aneurysms or occlusive lesions appears not to result from an ongoing difference in the proteolytic activities, but from differences in other factors, as-yet-undefined, including the distribution of MMPs expression within the aortic walls.