Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits.
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.


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.
Liang
Jingyan
J
Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
Liu
Enqi
E
Yu
Ying
Y
Kitajima
Shuji
S
Koike
Tomonari
T
Jin
Yingji
Y
Morimoto
Masatoshi
M
Hatakeyama
Kinta
K
Asada
Yujiro
Y
Watanabe
Teruo
T
Sasaguri
Yasuyuki
Y
Watanabe
Shigeyuki
S
Fan
Jianglin
J
D000818:Animals; D030801:Animals, Genetically Modified; D050197:Atherosclerosis / Q000209:etiology*; D002465:Cell Movement; D003324:Coronary Artery Disease / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000032:analysis; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000032:analysis / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011817:Rabbits
D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12