Effects of tissue inhibitor of metalloproteinase 2 deficiency on aneurysm formation

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Objective: Matrix metalloproteinase (MMP)-2 has been shown to play a pivotal role in aortic aneurysm formation. Its activation requires formation of a trimolecular complex of MMP-2, tissue inhibitor of metalloproteinase-2 (TIMP-2), and membrane type 1 (MT1)-MMP, which is attached to the cell surface. At higher concentrations, TIMP-2 becomes an inhibitor of MMP-2. Thus, TIMP-2 could both augment and inhibit matrix degradation. This study was undertaken to define the net effect of TIMP-2 on matrix destruction and aneurysm formation. Methods: The abdominal aortas of wild-type and TIMP-2-deficient (TIMP-2-/-) mice were exposed to 0.25 mol/L CaCl2 or 0.9% NaCl for 15 minutes after laparotomy. Aortic diameters were measured before treatment and 6 weeks after aneurysm induction. In addition, aortic tissues were studied for MMP-2 activation by zymography, and matrix structure was studied by connective tissue staining. Results: The aortic diameter increased in both wild-type and TIMP-2-/- mice. The increase in the TIMP-2-/- mice was significantly smaller after CaCl2 treatment (51% ± 3%) compared with the diameter of wild-type mice (67% ± 4%). Connective staining of aortic sections from the CaCl2-treated mice revealed disruption and fragmentation of the medial elastic lamellae in both wild-type and TIMP-2-/- mice. Zymographic analysis showed that active MMP-2 levels were decreased in TIMP-2-/- aortas compared with wild-type mice. Conclusions: Targeted deletion of TIMP-2 results in attenuation of aneurysm development. Despite its name as an inhibitor of MMPs, TIMP-2 promotes aortic enlargement in vivo, presumably through its role as a cofactor in the activation of MMP-2.

Original languageEnglish (US)
Pages (from-to)1061-1066
Number of pages6
JournalJournal of vascular surgery
Volume44
Issue number5
DOIs
StatePublished - Nov 1 2006

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Tissue Inhibitor of Metalloproteinase-2
Aneurysm
Matrix Metalloproteinase 2
Staining and Labeling
Matrix Metalloproteinase 14
Matrix Metalloproteinase Inhibitors
Aortic Aneurysm
Abdominal Aorta
Connective Tissue
Laparotomy
Names
Aorta

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

Effects of tissue inhibitor of metalloproteinase 2 deficiency on aneurysm formation. / Xiong, Wanfen; Knispel, Rebecca; Mactaggart, Jason N; Baxter, Bernard Timothy.

In: Journal of vascular surgery, Vol. 44, No. 5, 01.11.2006, p. 1061-1066.

Research output: Contribution to journalArticle

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abstract = "Objective: Matrix metalloproteinase (MMP)-2 has been shown to play a pivotal role in aortic aneurysm formation. Its activation requires formation of a trimolecular complex of MMP-2, tissue inhibitor of metalloproteinase-2 (TIMP-2), and membrane type 1 (MT1)-MMP, which is attached to the cell surface. At higher concentrations, TIMP-2 becomes an inhibitor of MMP-2. Thus, TIMP-2 could both augment and inhibit matrix degradation. This study was undertaken to define the net effect of TIMP-2 on matrix destruction and aneurysm formation. Methods: The abdominal aortas of wild-type and TIMP-2-deficient (TIMP-2-/-) mice were exposed to 0.25 mol/L CaCl2 or 0.9{\%} NaCl for 15 minutes after laparotomy. Aortic diameters were measured before treatment and 6 weeks after aneurysm induction. In addition, aortic tissues were studied for MMP-2 activation by zymography, and matrix structure was studied by connective tissue staining. Results: The aortic diameter increased in both wild-type and TIMP-2-/- mice. The increase in the TIMP-2-/- mice was significantly smaller after CaCl2 treatment (51{\%} ± 3{\%}) compared with the diameter of wild-type mice (67{\%} ± 4{\%}). Connective staining of aortic sections from the CaCl2-treated mice revealed disruption and fragmentation of the medial elastic lamellae in both wild-type and TIMP-2-/- mice. Zymographic analysis showed that active MMP-2 levels were decreased in TIMP-2-/- aortas compared with wild-type mice. Conclusions: Targeted deletion of TIMP-2 results in attenuation of aneurysm development. Despite its name as an inhibitor of MMPs, TIMP-2 promotes aortic enlargement in vivo, presumably through its role as a cofactor in the activation of MMP-2.",
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