Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits

J Liang, E Liu, Y Yu, S Kitajima, T Koike, Y Jin… - Circulation, 2006 - Am Heart Assoc
J Liang, E Liu, Y Yu, S Kitajima, T Koike, Y Jin, M Morimoto, K Hatakeyama, Y Asada…
Circulation, 2006Am Heart Assoc
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 …
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.
Am Heart Assoc