Macrophage elastase (MMP‐12) accelerates the progression of atherosclerosis in transgenic rabbits

Abstract

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.