Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis

Nooijer, Ramon de; Verkleij, Chantal J. N.; Thüsen, Jan H. von der; Jukema, J. Wouter; Wall, E. E. van der; Berkel, Thüsen J C van; Baker, Andrew H.; Biessen, E.A.L.

doi:10.1161/01.atv.0000197795.56960.64

Cited by 198 publications

(133 citation statements)

References 44 publications

Supporting

Mentioning

122

Contrasting

Unclassified

Order By: Relevance

“…Similarly, increased expression of MMP-3, MMP-12, and MMP-13 has been reported not only in atherosclerotic lesions but also in aneurysms in LDLR 2/2 (26). In ApoE 2/2 , overexpression of MMP-9 in macrophages has been observed in advanced atherosclerotic lesions and is commonly associated with plaque rupture (27) and intraplaque hemorrhage (28). Conversely, in ApoE 2/2 , MMP-9 deficiency is reported to be associated with reduced atherosclerosis, medial layer attenuation (29), and vascular remodeling (30).…”

Section: Discussionmentioning

confidence: 99%

Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor

Ohshima

Petrov²,

Fujimoto³

et al. 2009

J Nucl Med

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques and play an important role in plaque instability. Methods: Using 99m Tc-labeled broad-spectrum MMP inhibitor (MPI), we performed noninvasive imaging of MMP expression with micro-SPECT/micro-CT in mice deficient in apolipoprotein E (ApoE 2/2 , n 5 14), mice deficient in low-density-lipoprotein receptor (LDLR 2/2 , n 5 14), and C57/BL6 mice as controls (n 5 7). Seven ApoE 2/2 and 7 LDLR 2/2 received a high-cholesterol diet. After in vivo imaging, aortas were explanted, ex vivo images acquired, and the percent injected dose of MPI per gram (%ID/g) determined, followed by histologic characterization of atherosclerotic lesions. Results: MPI uptake was noninvasively visualized in atherosclerotic lesions by micro-SPECT, with confirmation by micro-CT of anatomic location and aortic calcification. %ID/g in each part of the aorta was highest in ApoE 2/2 that were fed a high-cholesterol diet, followed by LDLR 2/2 that were fed a high-cholesterol diet, ApoE 2/2 that were fed normal chow, and LDLR 2/2 that were fed normal chow. The control mice had minimal MPI uptake. A significant correlation was noted between %ID/g and % area positive for macrophages (r 5 0.81, P 5 0.009), MMP-2 (r 5 0.65, P 5 0.013), and MMP-9 (r 5 0.62, P 5 0.008). Conclusion: This study demonstrates the usefulness of molecular imaging for noninvasive assessment of the extent of MMP expression in various transgenic mouse models of atherosclerosis receiving a normal or hyperlipidemic diet. It is conceivable that such a strategy may be translationally developed for identification of unstable atherosclerotic plaques.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor

Ohshima

Petrov²,

Fujimoto³

et al. 2009

J Nucl Med

View full text Add to dashboard Cite

show abstract

“…However, over-expressing a mutated form of MMP-9 that becomes fully auto-activated produced high levels of plaque instability (19). Adenovirus-mediated over-expression of MMP-9 produced instability of advanced plaques caused by collar implantation into ApoE null mice (20). These studies illustrate an important principle: both the nature of MMPs expressed and the level of activity are crucial in determining whether controlled remodelling or matrix destruction and hence instability occurs.…”

Section: Intravascular Biology Meeting 2008mentioning

confidence: 96%

Vulnerable atherosclerotic plaque metalloproteinases and foam cell phenotypes

Newby

George²,

Ismail³

et al. 2009

Thromb Haemost

138

View full text Add to dashboard Cite

SummaryPlaque rupture underlies most myocardial infarctions. Plaques vulnerable to rupture have thin fibrous caps, an excess of macrophages over vascular smooth muscle cells, large lipid cores, and depletion of collagen and other matrix proteins form the cap and lipid core. Production of matrix metalloproteinases from macrophages is prominent in human plaques, and studies in genetically modified mice imply a causative role for metalloproKeywords Atherosclerosis, atherothrombosis, extracellular matrix, inflammation, matrix metalloproteinases teinases in plaque vulnerability. Recent in-vitro studies on human monocyte-derived macrophages and on foam-cell macrophages generated in vivo suggest the existence of several macrophage phenotypes with distinct patterns of metalloproteinase expression. These phenotypes could play differing roles in cap, core and aneurysm formation. There are more than 200,000 cases of myocardial infarction (MI) in the UK alone each year, and almost half this number of patients dies (http//:www.heartsats.org). MI results from coronary thrombosis at the site of an atherosclerotic plaque caused either by detachment of a large patch of surface endothelial cells or, more often, from rupture of the plaque cap. The characteristic features of ruptured plaques are: a thin fibrous cap; a higher ratio of macrophages to vascular smooth muscle cells (VSMCs) in the cap; less collagen, the main strength-giving component, in the cap; and a large, lipid-rich, collagen-poor necrotic core (1). The implication is that production of extracellular proteases from inflammatory cells degrades collagen and leads to mechanical weakness of the cap, particularly in the shoulder regions, which suffer high strain when the core is large and flexible (2). Intact plaques with the features of ruptured plaques listed above are believed vulnerable to subsequent rupture (vulnerable plaques), and patients with such plaques are thought vulnerable to MI (vulnerable patients). If so, pharmacological agents that reverse the features of vulnerable plaque will prevent MIs. So far this concept appears to hold true at least for statin drugs, which reduce the incidence of MI in clinical trials (3) and have biological effects such as inhibiting macrophage activation and protease production. Statins also reduce systemic and local plaque inflammation (4), the size of the lipid-rich necrotic core measured by magnetic resonance imaging (5), and the frequency of high-strain regions of the plaque cap measured by palpography in man (6). The present hope is to identify additional, maybe even more effective treatments to reverse plaque vulnerability and thereby prevent MIs. Role of matrix metalloproteinases (MMPs) in plaque vulnerabilityLoss of collagen and other extracellular matrix (ECM) components occurs in the highly-inflamed regions of plaque cap thereby reducing tensile strength; it also occurs in the lipid core, which promotes transfer of hydrodynamic forces during the cardiac cycle to the high-strain, shoulder regions of the plaque. For thi...

show abstract

“…114 Thus, the results appear to differ depending on whether endogenous MMP-9 is deleted, 112 or exogenous MMP-9 is overexpressed in the lesions. 113,114 Overexpressing either TIMP-1 or TIMP-2 by systemic injection of adenovirus, Johnson and colleagues showed that TIMP-2 but not TIMP-1 inhibited plaque rupture. 106 A limitation of most of these studies is that rupture was reported at only one location in the arterial system, and it is not certain whether similar rupture events occur elsewhere.…”

Section: Mmps and Plaque Rupturementioning

confidence: 99%

Collagens in the progression and complications of atherosclerosis

et al. 2009

View full text Add to dashboard Cite

Collagens constitute a major portion of the extracellular matrix in the atherosclerotic plaque, where they contribute to the strength and integrity of the fibrous cap, and also modulate cellular responses via specific receptors and signaling pathways. This review focuses on the diverse roles that collagens play in atherosclerosis; regulating the infiltration and differentiation of smooth muscle cells and macrophages; controlling matrix remodeling through feedback signaling to proteinases; and influencing the development of atherosclerotic complications such as plaque rupture, aneurysm formation and calcification. Expanding our understanding of the pathways involved in cell-matrix interactions will provide new therapeutic targets and strategies for the diagnosis and treatment of atherosclerosis.

show abstract

Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions But Not at Earlier Stages of Atherogenesis

Cited by 198 publications

References 44 publications

Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor

Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor

Vulnerable atherosclerotic plaque metalloproteinases and foam cell phenotypes

Collagens in the progression and complications of atherosclerosis

Contact Info

Product

Resources

About