Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits
Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits
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DOI：
10.1161/circulationaha.105.596031
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发表时间：
2006-04-25
期刊：
影响因子：
37.8
通讯作者：
Fan, JL
中科院分区：
文献类型：
--
作者：
Liang, JY;Liu, EQ;Fan, JL
背景：巨噬细胞金属弹性酶(MMP12)在动脉粥样硬化病变和动脉瘤中表达上调，因此，MMP12活性升高可能在动脉粥样硬化的发病机制中起重要作用。然而，基质金属蛋白酶-12在动脉粥样硬化发生和发展中的病理作用尚未明确。方法和结果：我们比较了高脂饮食诱导动脉粥样硬化的易感性和非转基因兔的敏感性。通过含有不同量胆固醇的饮食，兔子在较短时间内保持相对较低的高胆固醇血症，或在较长时间内保持较高水平的高胆固醇血症。我们发现在较低的高胆固醇血症下，甘油三酯和非甘油三酯兔的动脉粥样硬化病变的大小和质量没有显著差异。然而，在较高的高胆固醇血症的较长时间内，TG兔比非TG兔在主动脉和冠状动脉形成更广泛的动脉粥样硬化。组织学检查显示，TG兔动脉粥样硬化病变有明显的巨噬细胞浸润，并伴有中膜弹力层的明显断裂，偶有动脉瘤样病变形成。此外，巨噬细胞来源的基质金属蛋白酶-12的高表达与基质金属蛋白酶-3的高表达有关，提示基质金属蛋白酶-12可能在其他基质金属蛋白酶的级联激活中起关键作用，从而在动脉粥样硬化的发展过程中加剧细胞外基质的降解。这些结果提示巨噬细胞来源的基质金属蛋白酶-12参与了动脉粥样硬化的进展。
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.