Overexpression of MMP-12 in transgenic rabbits accelerated the progression of atherosclerosis in the aortas and coronary arteries compared to non-transgenic littermates at higher hypercholesterolemia.
Does overexpression of MMP-12 accelerate the progression of atherosclerosis in a transgenic rabbit model?
Macrophage-derived MMP-12 overexpression accelerates atherosclerosis progression and extracellular matrix degradation in a transgenic rabbit model.
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.
Liang et al. (Mon,) conducted a other in Atherosclerosis. MMP-12 overexpression (transgenic model) vs. Non-transgenic littermate rabbits was evaluated on Atherosclerotic lesion size and quality in the aortas and coronary arteries. Overexpression of MMP-12 in transgenic rabbits accelerated the progression of atherosclerosis in the aortas and coronary arteries compared to non-transgenic littermates at higher hypercholesterolemia.