ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis
Vincent Lemaître, … , Alan R. Tall, Jeanine D’Armiento
Vincent Lemaître, … , Alan R. Tall, Jeanine D’Armiento
Published May 15, 2001
Citation Information: J Clin Invest. 2001;107(10):1227-1234. https://doi.org/10.1172/JCI9626.
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Article

ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis

Abstract

Matrix metalloproteinase-1 (MMP-1), or interstitial collagenase, has been hypothesized to contribute to the progression of the human atherosclerotic lesions by digesting the fibrillar collagens of the neointimal ECM. The apolipoprotein E knockout (apoE0) mouse model develops complex atherosclerotic lesions, but mice do not possess a homologue for MMP-1. To provide an in vivo evaluation of the role of MMP-1 in atherogenesis, we created a transgenic mouse model that expresses this enzyme specifically in the macrophage, under the control of the scavenger receptor A (SCAV) enhancer/promoter. The MMP-1 transgenic mice were crossed into the apoE0 background and fed an atherogenic diet for 16–25 weeks. Surprisingly, the transgenic mice demonstrated decreased lesion size compared with control littermates. The lesions of the transgenic animals were less extensive and immature, with fewer cellular layers and a diminished content of fibrillar collagen. There was no evidence of plaque rupture. Our data suggest that remodeling of the neointimal extracellular matrix by MMP-1 is beneficial in the progression of lesions.

Authors

Vincent Lemaître, Timothy K. O’Byrne, Alain C. Borczuk, Yasunori Okada, Alan R. Tall, Jeanine D’Armiento

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Figure 3

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Presence of human MMP-1 in the atherosclerotic lesions of transgenic mic...
Presence of human MMP-1 in the atherosclerotic lesions of transgenic mice. (a) Western blot analysis of the aortic proteins from apoE0 (C) and transgenic MMP-1/apoE0 (Tg) mice using a rabbit polyclonal antibody against human MMP-1. Fifty micrograms of proteins were loaded on the gel. A signal of Mr 55,000 corresponding to MMP-1 is detected in the extract from the transgenic mouse. (b) RT-PCR. One microgram of total RNA isolated from the aorta of a transgenic MMP-1/apoE0 mouse was used for RT-PCR using primers designed from exons 9 and 10 of the human MMP-1 gene. The expected size of 619 bp was detected (Tg). No signal was detected when the reverse transcriptase was replaced with Taq polymerase (C). The PCR product from genomic DNA shows the expected size of 819 bp. M = molecular weight marker. (c) Immunohistochemical detection of MMP-1. Sections of the proximal aortas from apoE0 and transgenic MMP-1/apoE0 mice that were fed a Western diet for 16 weeks were incubated with a mouse mAb raised against human MMP-1. Scale bar: 50 μm.