Abstract
ObjectivesElevated matrix metalloproteinase-2 (MMP-2) tissue levels have been associated with ascending thoracic aortic aneurysm (aTAA). As MMP-2 activation is controlled by interactions among matrix metalloproteinase-14 (MMP-14), a tissue inhibitor of metalloproteinases-2 (TIMP-2) and Pro-MMP-2 in cell culture, this activation process might also play a role in aTAA.MethodsVia gelatin zymography we analyzed tissue levels of MMP-2 isoforms (Pro-MMP-2, active MMP-2, total MMP-2) and via enzyme-linked immunosorbent assay (ELISA,) MMP-14,TIMP-2 and total MMP-2 tissue levels in N = 42 patients with aTAA. As controls, MMP-14 and TIMP-2 aortic tissue levels in N = 9 patients undergoing coronary artery bypass surgery were measured via ELISA, and levels of MMP-2 isoforms in N = 11 patients via gelatin zymography.ResultsActive MMP-2 was significantly higher in aTAA than in controls. Patients with aTAA exhibited significantly lower Pro-MMP-2 and TIMP-2 levels. Total MMP-2 and MMP-14 did not differ significantly between groups. Regression analysis revealed a linear relationship between TIMP-2 and the MMP-14/TIMP-2 ratio, as well as active MMP-2 in aTAA. Aneurysmatic tissue can be accurately distinguished from control aortic tissue (AUC = 1) by analyzing the active MMP-2/Pro-MMP-2 ratio with a cutoff value of 0.11, whereas MMP-14 and TIMP-2 roles are negligible in ROC analysis.ConclusionA larger amount of MMP-2 is activated in aTAA than in control aortic tissue–a factor that seems to be a central process in aneurysm development. When active MMP-2 exceeds 10% compared to Pro-MMP-2, we conclude that it originates from aneurysmatic tissue, which we regard as a starting point for further studies of aTAA biomarkers. The tissue's MMP-14/TIMP-2 ratio may regulate the degree of Pro-MMP-2 activation as a determining factor, while the enzymatic activities of MMP-14 and TIMP-2 do not seem to play a key role in aneurysm development.
Highlights
Thoracic aortic aneurysmsAscending thoracic aortic aneurysms remain an important challenge in terms of intervention time and screening methods in cardiovascular surgery
Aneurysmatic tissue can be accurately distinguished from control aortic tissue (AUC = 1) by analyzing the active matrix metalloproteinase-2 (MMP-2)/Pro-Matrix metalloproteinases (MMPs)-2 ratio with a cutoff value of 0.11, whereas matrix metalloproteinase-14 (MMP-14) and tissue inhibitor of metalloproteinases-2 (TIMP-2) roles are negligible in receiver operating characteristic (ROC) analysis
A larger amount of MMP-2 is activated in ascending thoracic aortic aneurysm (aTAA) than in control aortic tissue–a factor that seems to be a central process in aneurysm development
Summary
Ascending thoracic aortic aneurysms (aTAA) remain an important challenge in terms of intervention time and screening methods in cardiovascular surgery. They are usually a silent disease, with the first symptom often an aortic rupture or aortic dissection—potentially deadly complications. Numerous studies report that aortic diameter alone does not seem to be a reliable indicator for surgery for aTAA, as some patients with an aneurysm exceeding intervention thresholds live for years without suffering an aortic dissection or rupture of their aneurysm, [3,4]. It is essential to accurately understand the pathogenesis of aTAA and evaluate markers revealing the risk of rupture or dissection other than aortic diameter alone
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