Early MT-1 MMP expression following elastase exposure is associated with increased cleaved MMP-2 activity in experimental rodent aortic aneurysms

Sinha, Indranil; Hannawa, Kevin K.; Eliason, Jonathan L.; Ailawadi, Gorav; Deogracias, Michael P.; Bethi, Siddharth; Ford, John W.; Roelofs, Karen J.; Grigoryants, Vladimir; Henke, Peter K.; Stanley, James C.; Upchurch, Gilbert R.

doi:10.1016/j.surg.2004.04.010

Cited by 31 publications

(41 citation statements)

References 22 publications

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“…To examine the potential contribution of MT1-MMP to AAA, expression levels of MT1-MMP in the aneurysm tissue of CaCl 2 -treated wild-type mice were compared with aortic tissue from sham, NaCl-treated controls by RT-PCR. Consistent with reports documenting increased MT1-MMP levels in human aneurysm tissue (21,22), mouse MT1-MMP mRNA levels were likewise increased in aneurysmal aorta tissue relative to nonaneurysmal controls (Fig. 1A).…”

Section: Resultssupporting

confidence: 90%

Membrane-type 1 Matrix Metalloproteinase Regulates Macrophage-dependent Elastolytic Activity and Aneurysm Formation in Vivo

Xiong

Knispel

MacTaggart

et al. 2009

Journal of Biological Chemistry

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During arterial aneurysm formation, levels of the membraneanchored matrix metalloproteinase, MT1-MMP, are elevated dramatically. Although MT1-MMP is expressed predominately by infiltrating macrophages, the roles played by the proteinase in abdominal aortic aneurysm (AAA) formation in vivo remain undefined. Using a newly developed chimeric mouse model of AAA, we now demonstrate that macrophage-derived MT1-MMP plays a dominant role in disease progression. In wild-type mice transplanted with MT1-MMP-null marrow, aneurysm formation induced by the application of CaCl 2 to the aortic surface was almost completely ablated. Macrophage infiltration into the aortic media was unaffected by MT1-MMP deletion, and AAA formation could be reconstituted when MT1-MMP ؉/؉ macrophages, but not MT1-MMP ؉/؉ lymphocytes, were infused into MT1-MMP-null marrow recipients. In vitro studies using macrophages isolated from either WT/MT1-MMP ؊/؊ chimeric mice, MMP-2-null mice, or MMP-9-null mice demonstrate that MT1-MMP alone plays a dominant role in macrophage-mediated elastolysis. These studies demonstrate that destruction of the elastin fiber network during AAA formation is dependent on macrophage-derived MT1-MMP, which unexpectedly serves as a direct-acting regulator of macrophage proteolytic activity. Development and progression of abdominal aortic aneurysm (AAA)2 is a complex process that, untreated, can lead to tissue failure, hemorrhage, and death (1). Destruction of the orderly elastin lamellae of the vessel wall is considered the sine qui non of arterial aneurysm formation (2) as adult tissues cannot regenerate normal elastin fibers (3). Moreover, the elastin degradation products are chemotactic for inflammatory cells and serve to amplify the local injury (4). Although several types of elastolytic proteases are elevated in AAA tissue (5-9), studies using murine models of AAA and targeted protease deletion suggest that matrix metalloproteinases (MMPs), particularly the secreted proteases, MMP-2 and MMP-9, play key roles in the pathologic remodeling of the elastin lamellae that lead to AAA (7,8).Membrane-type 1 MMP (MT1-MMP) is the prototypical member of a family of membrane-tethered MMPs (10). Recent studies indicate that MT1-MMP expression is elevated in human AAA tissues and that infiltrating macrophages are the primary source of the proteinase in aortic lesions (11-13). Although indirect evidence suggests that MT1-MMP may participate in the control of monocyte/macrophage motile responses as well as interactions with the vessel wall during transmigration (14, 15), the role(s) played by MT1-MMP in regulating macrophage proteolytic activity or AAA formation in vivo remains undefined.Using a murine model of AAA and mice with a targeted deletion of MT1-MMP in myelogenous cell populations, we now demonstrate that macrophage-derived MT1-MMP is required for elastin degradation and aneurysm formation. Importantly, macrophages are not dependent on MT1-MMP for infiltrating aortic tissues but instead use the protease to directly regulate th...

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Section: Resultssupporting

confidence: 90%

Membrane-type 1 Matrix Metalloproteinase Regulates Macrophage-dependent Elastolytic Activity and Aneurysm Formation in Vivo

Xiong

Knispel

MacTaggart

et al. 2009

Journal of Biological Chemistry

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“…It is now becoming recognized that alterations in a specific ECM proteolytic cascade involving the MMPs and their endogenous inhibitors (TIMPs) occur in cardiovascular disease states such as abdominal aortic aneurysms as well as ATAAs. [7][8][9][10][11][12][13][14] However, a comparative quantitative profile of MMPs and TIMPs that occurs within ATAAs in MFS with respect to ATAAs in non-MFS patients and normal ascending aortic tissue has not been performed. In addition, recent evidence has implicated TGF-␤ activation in the pathogenesis of aortic dilatation seen with MFS.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11][12][13][14][15] MMPs are synthesized by numerous cells including smooth muscle and endothelial cells, fibroblasts, neutrophils, and macrophages as inactive pro-forms that require subsequent cleavage for activation. 10,23 In addition to the ECM, MMPs have numerous other substrates, including other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors (such as TGF-␤), growth factor-binding proteins, cell surface receptors, cell-cell adhesion molecules, pro-inflammatory cytokines such as IL-1, and TNF-␣.…”

Section: Discussionmentioning

confidence: 99%

“…Each member of the TIMP family exhibits a distinct pattern of affinity for particular MMPs through a reversible, 1:1 interaction, 10,16 and stoichiometric shifts between MMPs and TIMPs have been shown to favor abdominal aortic aneurysm formation. 15 In addition, TIMPs have a number of other effects including activation of other MMPs, 14,16 potentiation of growth factors, 16 and instigation or suppression of apoptosis. 16 In the present study, a complete survey of all 4 TIMPs was undertaken including TIMP-1, which is highly expressed in the aorta, 10 and TIMP-4, which is cardiovascular system-specific.…”

Section: I-368 Circulation July 4 2006mentioning

confidence: 99%

“…An association has been established between increases in MMPs and development of aortic aneurysms. [7][8][9][10][11][12][13][14] Primary endogenous control of MMP activity is maintained through 4 tissue inhibitors of metalloproteinases (TIMPs). 10,15,16 In aortic aneurysms, imbalances in the ambient MMP:TIMP ratio within the aortic wall are observed, which favor net proteolysis.…”

mentioning

confidence: 99%

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