Published online before print December 23, 2002, doi: 10.1161/01.CIR.0000044915.37074.5C
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(Circulation. 2003;107:333.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E–Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1
From the Division of Molecular Medicine (V.L., J.D.), Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, and the Division of Nutritional Sciences, Cornell University (P.D.S.), Ithaca, NY.
Correspondence to Jeanine D’Armiento, Columbia University, Department of Medicine, P&S 8-401, 630 W 168th St, New York, NY 10032. E-mail jmd12{at}columbia.edu
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-/-) 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-/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-/0/apoE0 mice averaged 1.9±1.2 medial ruptures in the proximal aorta, compared with 0.5±0.7 for the apoE0 controls (P<0.003). 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.
Key Words: mouse • metalloproteinases • atherosclerosis
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