Published online before print April 10, 2008

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(American Journal of Pathology. 2008;172:1419-1429.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070604

Matrix Metalloproteinase 12 Accelerates the Initiation of Atherosclerosis and Stimulates the Progression of Fatty Streaks to Fibrous Plaques in Transgenic Rabbits

Sohsuke Yamada^*, Ke-Yong Wang^*, Akihide Tanimoto^*, Jianglin Fan, Shohei Shimajiri^*, Shuji Kitajima, Masatoshi Morimoto, Masato Tsutsui^¶, Teruo Watanabe^||, Kosei Yasumoto and Yasuyuki Sasaguri^*

From the Departments of Pathology and Cell Biology,^* Surgery, and Pharmacology,^¶ School of Medicine, University of Occupational and Environmental Health, Kitakyushu; the Department of Molecular Pathology, Faculty of Medicine, University of Yamanashi, Yamanashi; the Analytical Research Center for Experimental Sciences, Saga University, Saga; and the Kyurin Omtest Laboratory Department,|| Kyurin Corporation, Kitakyushu, Japan

Whether fatty streaks are directly followed by fibrous plaque formation in atherosclerosis remains controversial. Disruption of the basement membrane and elastic layers is thought to be essential for this process. Matrix metalloproteinase 12 (MMP-12) can degrade a broad spectrum of substrates, but the role of MMP-12 in the early stage of atherosclerosis is unclear. To investigate MMP-12 function in the initiation and progression of atherosclerosis, we investigated macrophage migration and elastolysis in relation to fatty streaks in human MMP-12 transgenic (hMMP-12 Tg) rabbits. Fatty streaks in hMMP-12 Tg rabbits fed a 1% cholesterol diet for 6 weeks (cholesterol-induced model of atherosclerosis) were more pronounced and were associated with more significant degradation of the internal elastic layer compared with wild-type (WT) animals. Numbers of infiltrating macrophages and smooth muscle cells in the lesions were increased in hMMP-12 Tg compared with WT animals. In both cuff- and ligation-induced models of atherosclerosis, smooth muscle cell-predominant atherosclerotic lesions were elevated with significant elastolysis of the internal elastic lamina in Tg compared with WT animals; "microelastolytic sites" were recognized before formation of the neointima in the cuff model only. These results indicate that MMP-12 may be critical to the initiation and progression of atherosclerosis via degradation of the elastic layers and/or basement membrane. Therefore, a specific MMP-12 inhibitor might prove useful for the treatment of progressive atherosclerosis.

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