Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model.

Allaire, Éric; Forough, Reza; Clowes, Monika M.; Starcher, Barry; Clowes, Alexander W.

doi:10.1172/jci2909

Cited by 279 publications

(220 citation statements)

References 49 publications

(46 reference statements)

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“…30 Experiments in rats demonstrated that the retroviral overexpression of TIMP-1 in smooth muscle cells prevented the degradation of the media, a process associated with decreased MMP activity. 13 Because we did not detect differences in plaque size, macrophage content, and collagen deposition between controls and Timp-1 Ϫ/0 animals after 10 weeks of high-fat diet, it appears that TIMP-1 deficiency alone does not significantly alter plaque evolution or progression. In a previous study, we have shown that increased expression of the human enzyme MMP-1 (interstitial collagenase) in plaques led to decreased lesion formation in apoE0 animals.…”

Section: Discussionmentioning

confidence: 70%

“…10 Previous studies have suggested that TIMP-1 might play an important role in the development of atherosclerotic lesions 12 and in vessel wall degeneration. 13 To study the role of TIMP-1 in atherosclerosis, we crossed the Timp-1-knockout mouse into the atherosclerosis-susceptible apoE-knockout background. 14,15 The hypercholesterolemic apoE0 mice develop lesions of atherosclerosis that are similar to human lesions but do not rupture.…”

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confidence: 99%

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Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E–Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1

2003

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Background-The tissue inhibitor of metalloproteinases-1 (TIMP-1) is expressed in atherosclerotic lesions, where it may play a critical role in regulating the activity of matrix metalloproteinases (MMPs). Several MMPs are overexpressed in the atherosclerotic plaque, and they are believed to contribute to the expansion and rupture of the lesion. Methods and Results-The Timp-1-knockout mouse model (Timp-1 Ϫ/Ϫ ) was crossed into the apolipoprotein E-knockout (apoE0) background. A study population of male apoE0 mice, half of them deficient in TIMP-1, was fed an atherogenic diet. After 10 weeks of the diet, the mean lesion sizes of the two groups of animals were not significantly different, and the average content of fibrillar collagen and macrophages in the lesions was similar. There was no sign of plaque hemorrhage, even after 22 weeks of high-fat diet, indicating that deficiency in TIMP-1 does not predispose to luminal rupture. However the atherosclerotic lesions of the Timp-1 Ϫ/0 mice developed more aortic medial ruptures, in which all elastic lamellae of the media were degraded and infiltrated with macrophages, forming pseudo-microaneurysms. After 10 weeks of high-fat diet, the Timp-1 Ϫ/0 /apoE0 mice averaged 1.9Ϯ1.2 medial ruptures in the proximal aorta, compared with 0.5Ϯ0.7 for the apoE0 controls (PϽ0.003). At the site of degradation, in situ zymography revealed that the gelatinolytic activity, mainly associated with macrophages, could be abolished by the addition of MMP inhibitors. Conclusions-These data strongly suggest that TIMP-1 plays a key role in preventing medial degradation associated with atherosclerosis through its ability to inhibit the MMPs that are involved in the disruption of the media.

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Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 99%

Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E–Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1

2003

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“…However, it is uncertain whether calcification is a marker for plaque instability [26]. Recent studies showing that pharmacological inhibition of MMPs attenuates ventricular dilation, increases collagen content, and stabilizes atherosclerotic plaque, lead us to speculate that TIMP-1, a natural inhibitor of MMPs, could well provide protection against plaque instability [13,27,28]. The observed correlation between TIMP-1 and increased type I collagen would also support a role for this inhibitor in the maintenance of vascular integrity.…”

Section: Discussionmentioning

confidence: 99%

“…MMP activity is controlled by specific inhibitors (TIMPs); four members of the tissue inhibitor family have been identified: TIMP-1, -2, -3, and -4 [11,12]. Their overexpression reduces neointimal development in experimental models of vascular injury and may provide protection against plaque destabilization [13,14].…”

Section: Introductionmentioning

confidence: 99%

Different expression of MMPs/TIMP-1 in human atherosclerotic lesions. Relation to plaque features and vascular bed

et al. 2003

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Background: Proteolytic imbalance might determine arterial remodeling and plaque destabilization in atherosclerotic vessels. The aim of this study was to examine differences in the patterns of metalloproteinases (MMPs) and MMP inhibitor (TIMP-1) expression in advanced human atheromas, both in relation to the plaque features and the vascular bed involved. Methods and results: Immunohistochemistry for MMP-1, -3, -9 and TIMP-1 as well as the collagen content were measured in vascular sections from patients undergoing peripheral revascularization (carotid n = 11, femoral n = 23) and aorto-coronary bypass surgery (mammary arteries n = 20, as controls). Increased expression of all MMPs was detected in atherosclerotic as compared with control sections (P<0.01). Aneurismal plaques showed a significant increase of MMP-1 and-3 and a reduction in total collagen (P<0.05) in relation to occlusive lesions. Calcification areas in atherosclerotic plaques were consistently associated with increased TIMP-1 expression (P<0.01). Finally, MMP-9 expression was higher in occlusive lesions from carotid than femoral arteries (P<0.01). Conclusions: Aneurysm lesions expressed higher MMP-1 and-3 expression than occlusive plaques, and MMP-9 was mainly detected in carotid as compared with femoral arteries. TIMP-1 was associated with arterial calcification. These differences in the MMPs/TIMP-1 expression might determine the evolution of advanced atherosclerotic plaques and contribute to its vulnerability.

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“…uPA deficiency reduced aneurism formation [10] while osteopontin is upregulated in aortic aneurisms [15]. Tissue inhibitor of metalloproteinases (TIMP) 1 binds and inactivates MMPs, while TIMP-2 protects MMPs from inactivation by TIMP-1; TIMP-1 overexpression [18] and TIMP-2 [19] deficiency reduced aneurism formation in mice.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

Tittiger

Knutsen

et al. 2008

Molecular Genetics and Metabolism

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Mucopolysaccharidosis I (MPS I), known as Hurler syndrome in the severe form, is a lysosomal storage disease due to -L-iduronidase (IDUA) deficiency. It results in fragmentation of elastin fibers in the aorta and heart valves via mechanisms that are unclear, but may result from the accumulation of the glycosaminoglycans heparan and dermatan sulfate. Elastin fragmentation causes aortic dilatation and valvular insufficiency, which can result in cardiovascular disease. The pathophysiology of aortic disease was evaluated in MPS I mice. MPS I mice have normal elastic fiber structure and aortic compliance at early ages, which suggests that elastin assembly is normal. Elastin fragmentation and aortic dilatation are severe at 6 months, which is temporally associated with marked increases in mRNA and enzyme activity for two elastin-degrading proteins, matrix metalloproteinase-12 (MMP-12) and cathepsin S. Upregulation of these genes likely involves activation of STAT proteins, which may be induced by structural stress to smooth muscle cells from accumulation of glycosaminoglycans in lysosomes. Neonatal intravenous injection of a retroviral vector normalized MMP-12 and cathepsin S mRNA levels and prevented aortic disease. We conclude that aortic dilatation in MPS I mice is likely due to degradation of elastin by MMP-12 and/or cathepsin S. This aspect of disease might be ameliorated by inhibition of the signal transduction pathways that upregulate expression of elastase proteins, or by inhibition of elastase activity. This could result in a treatment for patients with MPS I, and might reduce aortic aneurism formation in other disorders.

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Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model.

Cited by 279 publications

References 49 publications

Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E–Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1

Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E–Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1

Different expression of MMPs/TIMP-1 in human atherosclerotic lesions. Relation to plaque features and vascular bed

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

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