Expression and localization of matrix metalloproteinase-12 in the aorta of cholesterol-fed rabbits: relationship to lesion development

S Matsumoto, T Kobayashi, M Katoh, S Saito… - The American journal of …, 1998 - Elsevier
S Matsumoto, T Kobayashi, M Katoh, S Saito, Y Ikeda, M Kobori, Y Masuho, T Watanabe
The American journal of pathology, 1998Elsevier
Degradation of extracellular matrix (ECM) proteins in the aorta is a critical step for the
development of atherosclerosis. Expression of matrix metalloproteinase (MMP)-12
(macrophage elastase), an elastin-degrading proteinase in the MMP family, was
investigated in the thoracic aorta of rabbits fed a 1% cholesterol-containing diet for 16
weeks. In the atherosclerotic lesions, MMP-12 was produced abundantly at both the mRNA
and protein levels, whereas no expression was observed in the normal rabbit aortas. The …
Degradation of extracellular matrix (ECM) proteins in the aorta is a critical step for the development of atherosclerosis. Expression of matrix metalloproteinase (MMP)-12 (macrophage elastase), an elastin-degrading proteinase in the MMP family, was investigated in the thoracic aorta of rabbits fed a 1% cholesterol-containing diet for 16 weeks. In the atherosclerotic lesions, MMP-12 was produced abundantly at both the mRNA and protein levels, whereas no expression was observed in the normal rabbit aortas. The principal source of MMP-12 was macrophage foam cells (MFCs) that had infiltrated the atherosclerotic intima; this was demonstrated in both in vitro culture studies of MFCs purified from atherosclerotic lesions and immunohistochemical studies of aortic lesions. Additional biochemical studies using recombinant rabbit MMP-12 revealed that MMP-12 digested elastin, type IV collagen, and fibronectin and also activated MMP-2 and MMP-3. Expression of MMP-12 by human macrophage cell lines was increased by stimulation with acetylated low-density lipoprotein, implying augmentation of MMP-12 production during foam cell formation. Increased expression of MMP-12 in atherosclerotic lesions, concomitant with foam cell generation, which triggers the acceleration of ECM breakdown, is likely to be a critical step in the initiation and progression of the atherosclerotic cascade.
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