Matrix Metalloproteinase-8 and -9 Are Increased at the Site of Abdominal Aortic Aneurysm Rupture

Wilson, W.R.W.; Anderton, M.; Schwalbe, Edward C; Jones, J. Louise; Furness, Peter; Bell, P. R. F.; Thompson, Matthew M.

doi:10.1161/circulationaha.105.551572

Cited by 204 publications

(152 citation statements)

References 32 publications

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“…Our findings confirm and extend findings from Wilson and colleagues 47 but do not indicate increased MMP or cysteine collagenase expression in the anterior aneurysmal wall as the cause of rupture, 47,48 yet we cannot exclude that local increases in cysteine collagenase activities at the site of rupture contribute to rupture of the aneurysm. Reduced cystatin C protein expression along with increased collagen degradation products in the anterior aneurysmal wall of ruptured aneurysms points to an alternative mechanism and suggests that protease inhibitor deficiency rather than increased protease expression may contribute to AAA rupture.…”

Section: Discussionsupporting

confidence: 83%

Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

164

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Growth and rupture of abdominal aortic aneurysms (AAAs) result from increased collagen turnover . Collagen turnover critically depends on specific collagenases that cleave the triple helical region of fibrillar collagen. As yet , the collagenases responsible for collagen degradation in AAAs have not been identified. Increased type I collagen degradation products confirmed collagen turnover in AAAs (median values: <1 , 43 , and 108 ng/mg protein in control , growing , and ruptured AAAs , respectively). mRNA and protein analysis identified neutrophil collagenase [matrix metalloproteinase (MMP)-8] and cysteine collagenases cathepsin K , L , and S as the principle collagenases in growing and ruptured AAAs. Except for modestly increased MMP-14 mRNA levels , collagenase expression was similar in growing and ruptured AAAs (anteriorlateral wall). Evaluation of posttranslational regulation of protease activity showed a threefold increase in MMP-8 , a fivefold increase in cathepsins K and L , and a 30-fold increase in cathepsin S activation in growing and ruptured AAAs. The presence of the osteoclastic proton pump indicated optimal conditions for extracellular cysteine protease activity. Protease inhibitor mRNA expression was similar in AAAs and controls, but AAA protein levels of cystatin C, the principle cysteine protease inhibitor, were profoundly reduced (>80%). We found indications that this secondary deficiency relates to cystatin C degradation by (neutrophil-derived) proteases. Abdominal aortic aneurysm (AAA) is a common pathology and a major cause of death because of rupture. 1,2 The hallmark pathology of AAA is a persistent proteolytic imbalance that results in excess matrix destruction and progressive weakening of the arterial wall. A number of matrix metalloproteinases (MMPs) (in particular the gelatinases MMP-2 and -9) 1,3 have been implicated as primary proteolytic culprits in the disease, but it is dubious whether these proteases are directly responsible for the weakening and ultimate failure of the aortic wall. Biomechanical studies invariably show that the mechanical stability of the arterial wall essentially relies on fibrillar collagens in media and adventitia. 4 -6 These structural collagens are highly resistant toward proteolytic degradation, and the only mammalian proteases that have been shown to cleave the native triple helical region of fibrillar collagen are the classic collagenases of the MMP family 7 [ie, MMP-1, -8, and -13 and the membrane type-1 MMP (MT-1 MMP or MMP-14 8 )], as well as selected members of the cysteine protease family (ie, cathepsin K, 9,10 L, 11 and possibly S 12 ).Several reports indicate expression of these collagenases in AAA on an individual basis, but comparative data regarding expression of the collagenases, and their possible relationship to rupture of the aneurysm, 13,14 are not available. Moreover, available studies 15 do not address the critical and complex posttranslational regulation of protease activity that involves controlled secretion of an inactive proenzyme,...

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Section: Discussionsupporting

confidence: 83%

Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

164

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“…42,43 As the matrix protein degradation and subsequent weakening of the aortic wall are the chief features of AAA, the association of MMP activities and aneurysm has been established by many studies both in animal models 4,44 and in human. 45 MMPs are produced as zymogens mostly by activated macrophages in the vascular wall. Serine proteases uPA and plasmin was known to initiate the activation of proMMPs.…”

Section: Pai-1 Prevents Aaa Hs Qian Et Almentioning

confidence: 99%

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

Hs¹,

Jm²,

P³

et al. 2007

Gene Ther

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Vessel wall inflammation and matrix destruction are critical to abdominal aortic aneurysm (AAA) formation and rupture. We have previously shown that urokinase plasminogen activator (uPA) is highly expressed in experimental AAA and is essential for AAA formation and expansion. In this study, we examined the effects of overexpression of a natural inhibitor of uPA, plasminogen activator inhibitor-1 (PAI-1), on the development of angiotensin (Ang) II-induced AAA in ApoE-deficient (ApoE À/À ) mice. Mice were treated with recombinant adenovirus containing either the human PAI-1 gene (Ad5.CMV.PAI-1) or the luciferase gene (Ad5.CMV.Luc) delivered either locally by intra-adventitial injection or systemically by tail vein injection. Our results show that local delivery of the PAI-1 gene completely prevented AAA formation (0 vs 55.6% in Ad5.CMV.Luc controls, Po0.05). In contrast, systemic delivery of the PAI-1 gene did not affect AAA incidence (78 vs 90% in Ad5.CMV.Luc controls, P ¼ 0.125). Local delivery of the PAI-1 gene 2 weeks after Ang II infusion prevented further expansion of small aneurysms, but had no significant effect on the progression of larger aneurysms. These data suggest that local PAI-1 gene transfer could be used to stabilize small AAA and reduce the rate of expansion and risk of rupture.

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“…Macrophage-associated MMP-8 protein levels are increased at the rupture site of abdominal aorta aneurysm [9,10] compared to the normal aorta [11]. The amounts of both total and active MMP-8 are significantly higher in ruptured infarct tissue in patients with fatal myocardial infarction compared to the control infarct tissue [12].…”

Section: Introductionmentioning

confidence: 96%

The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence

Pussinen

Sarna

Puolakkainen

et al. 2013

International Journal of Cardiology

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The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence Pussinen, Pirkko J.; Sarna, Seppo; Puolakkainen, Mirja; Öhlin, Hans; Sorsa, Timo; Pesonen, Erkki Citation for published version (APA): Pussinen, P. J., Sarna, S., Puolakkainen, M., Öhlin, H., Sorsa, T., & Pesonen, E. (2013). The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence. International Journal of Cardiology, 167(2), 362-368. https://doi.org/10.1016/j.ijcard.2011.12.095 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractBackground Matrix metalloproteinase-8 (MMP-8) is involved in the breakdown of the extracellular matrix increasing the vulnerability of atherosclerotic lesions. We analyzed the diagnostic value of serum MMP-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations in acute coronary syndrome (ACS) and their prognostic value in ACS recurrence. MethodsThe population comprised 343 patients with ACS [including 108 unstable angina pectoris and 235 acute myocardial infarctions (AMI)] and 326 healthy controls. Additionally, 157 (45.8%) patients were resampled during the recovery. The ACS patients were followed up for 6 years.Results MMP-8, TIMP-1, and their molar ratio distinguished the cases from the controls; C-statistic of the multivariate model (95% CI, p-value) including the MMP-8/TIMP-1 ratio regarding its discriminating ability for AMI was 0.922 (0.893-0.950, p<0.001). After the acute phase of ACS, median MMP-8 and TIMP-1 concentrations decreased (p<0.001) by 34.5 and 28.7%, respectively, but ended up on a different level than those found in the controls. In the follow-up, acute phase and recovery period TIMP-1 concentrations associated with cardiovascular death with hazard ratios 4.31 (2.00-9.26, p<0.001) and 4.69 (1.10-20.01, p=0.037), respectively. ConclusionsThe increase of serum MMP-8 and TIMP-1 concentrations may reflect plaque instability and tissue damage. TIMP-1 concentrations are associated with poor outcome in patients with ACS. The findings may have practical implications in both diagnostics and therapeutics.

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Matrix Metalloproteinase-8 and -9 Are Increased at the Site of Abdominal Aortic Aneurysm Rupture

Abstract: A localized increase in MMP-8 and -9, mediated by native mesenchymal cells, presents a potential pathway for collagen breakdown and AAA rupture.

Cited by 204 publications

References 32 publications

Collagen Degradation in the Abdominal Aneurysm

Collagen Degradation in the Abdominal Aneurysm

Overexpression of PAI-1 prevents the development of abdominal aortic aneurysm in mice

The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence

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