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 1

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Expression of human MMP-1 in transgenic macrophages. (a) Tissue expressi...
Expression of human MMP-1 in transgenic macrophages. (a) Tissue expression pattern of human MMP-1 in transgenic mice. An RNase protection assay was performed using RNA isolated from peritoneal macrophages (Mφ), the heart, lung, aorta, liver, spleen, kidney, testis, and brain. Both wild-type (Wt) and transgenic (Tg) macrophages were analyzed. The unprotected probe is 842 nucleotides (nt), and the protected fragment is 585 nucleotides. (b) Western blot analysis of peritoneal macrophages culture media after activation with APMA. The activated human collagenase-1 (Mr 45,000) is detected only in the media from transgenic macrophages, not from wild-type. Macrophages from two transgenic and two wild-type mice were tested. Activated purified human interstitial collagenase (MMP-1) and culture medium alone (CM) were used as controls. (c) Collagenase activity in the culture media from transgenic and normal peritoneal macrophages. Culture media of peritoneal macrophages from two transgenic and two wild-type mice were activated with APMA and incubated with type I collagen. The characteristic 1/4 COOH-terminal fragments of the monomeric α1 and α2 chains from type I collagen, produced by MMP-1, are detected in the media from transgenic macrophages.