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(Circulation. 2006;113:1993-2001.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Macrophage Metalloelastase Accelerates the Progression of Atherosclerosis in Transgenic Rabbits

Jingyan Liang, MD^*; Enqi Liu, PhD^*; Ying Yu, MD; Shuji Kitajima, DVM; Tomonari Koike, PhD; Yingji Jin, MD; Masatoshi Morimoto, PhD; Kinta Hatakeyama, MD, PhD; Yujiro Asada, MD, PhD; Teruo Watanabe, MD, PhD; Yasuyuki Sasaguri, MD, PhD; Shigeyuki Watanabe, MD, PhD; Jianglin Fan, MD, PhD

From the Cardiovascular Disease Laboratory, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba (J.L., Y.Y., T.K., Y.J., J.F.); Analytical Research Center for Experimental Science, Saga University, Saga (E.L., S.K., M.M., T.W.); First Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki (K.H., Y.A.); Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Health, Kitakyushu (Y.S.); Division of Cardiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba (S.W.); and Department of Molecular Pathology, Faculty of Medicine, University of Yamanashi, Yamanashi (T.K., J.F.), Japan.

Correspondence to Jianglin Fan, Chairman and Professor, Department of Molecular Pathology, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo-City Yamanashi 409-3898, Japan. E-mail hisakoa{at}yamanashi.ac.jp

Received October 18, 2005; revision received January 18, 2006; accepted February 2, 2006.

Background— Macrophage metalloelastase (matrix metalloproteinase [MMP]-12) is upregulated in atherosclerotic lesions and aneurysm; thus, increased MMP-12 activity may play an important role in the pathogenesis of atherosclerosis. However, the pathological roles of MMP-12 in the initiation and progression of atherosclerosis have not been defined.

Methods and Results— 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 through a diet containing different amounts of cholesterol. We found no significant difference in the aortic atherosclerotic lesion size or quality between Tg and non-Tg rabbits at lower hypercholesterolemia. At higher hypercholesterolemia for longer periods, however, Tg rabbits developed more extensive atherosclerosis in the aortas and coronary arteries than did 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 with occasional formation of aneurysm-like lesions. Furthermore, increased expression of MMP-12 derived from macrophages was associated with elevated expression of MMP-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.

Conclusions— Overexpression of MMP-12 causes accelerated atherosclerosis in Tg rabbits. These results suggest that macrophage-derived MMP-12 participates in the progression of atherosclerosis.

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