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Macrophage elastase (MMP‐12) accelerates the progression of atherosclerosis in transgenic rabbits
Author(s) -
Fan Jianglin,
Liang Jingyan,
Yu Ying,
Koike Tomonari,
Kitajima Shuji,
Morimoto Masatoshi,
Watanabe Teruo
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a12-c
Subject(s) - matrix metalloproteinase , macrophage , pathological , coronary atherosclerosis , inflammation , lesion , cholesterol , medicine , genetically modified mouse , endocrinology , fatty streak , elastase , transgene , pathology , biology , coronary artery disease , in vitro , enzyme , biochemistry , gene
Macrophage metalloelastase (MMP‐12) has been hypothesized to contribute to the progression of human atherosclerotic lesions. However, the pathological roles of MMP‐12 in the initiation and progression of atherosclerosis have not been defined. To examine if MMP‐12 might participate in atherogenesis, we compared the susceptibility of MMP‐12 transgenic (Tg) rabbits to cholesterol‐rich diet‐induced atherosclerosis with that of non‐Tg littermate rabbits. The rabbits were maintained at either relatively lower levels of hypercholesterolemia for shorter periods or higher levels of hypercholesterolemia for longer periods via feeding a diet containing different amounts of cholesterol. Although there was no significant difference in the aortic atherosclerotic lesion size or quality between Tg and non‐Tg rabbits at lower hypercholesterolemia, Tg rabbits at higher hypercholesterolemia for longer periods developed more extensive atherosclerosis in the aortas as well as in the coronary arteries than non‐Tg rabbits. Histological examinations revealed that atherosclerotic lesions of Tg rabbits contained prominent macrophage infiltration associated with marked disruption of the elastic lamina in the tunica media. Furthermore, increased expression of MMP‐12 derived from macrophages was associated with elevated expression of MMP‐1 and ‐3, suggesting that MMP‐12 may play a pivotal role in the cascade activation of other MMPs, thereby exacerbating extracellular matrix degradation during the progression of atherosclerosis. Our data suggest that macrophage‐derived MMP‐12 directly participates in the progression of atherosclerosis.