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A potential key mechanism in ascending aortic aneurysm development: Detection of a linear relationship between MMP-14/TIMP-2 ratio and active MMP-2

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Listed:
  • Ramona Schmitt
  • Anke Tscheuschler
  • Philipp Laschinski
  • Xenia Uffelmann
  • Philipp Discher
  • Jana Fuchs
  • Maximilian Kreibich
  • Remi Peyronnet
  • Fabian A Kari

Abstract

Objectives: Elevated 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. Methods: Via 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. Results: Active 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. Conclusion: A 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.

Suggested Citation

  • Ramona Schmitt & Anke Tscheuschler & Philipp Laschinski & Xenia Uffelmann & Philipp Discher & Jana Fuchs & Maximilian Kreibich & Remi Peyronnet & Fabian A Kari, 2019. "A potential key mechanism in ascending aortic aneurysm development: Detection of a linear relationship between MMP-14/TIMP-2 ratio and active MMP-2," PLOS ONE, Public Library of Science, vol. 14(2), pages 1-17, February.
    • Handle: RePEc:plo:pone00:0212859
    DOI: 10.1371/journal.pone.0212859
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    1. Anke Tscheuschler & Philipp Meffert & Friedhelm Beyersdorf & Claudia Heilmann & Nadja Kocher & Xenia Uffelmann & Philipp Discher & Matthias Siepe & Fabian A Kari, 2016. "MMP-2 Isoforms in Aortic Tissue and Serum of Patients with Ascending Aortic Aneurysms and Aortic Root Aneurysms," PLOS ONE, Public Library of Science, vol. 11(11), pages 1-19, November.
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