Liang Jingyan, Liu Enqi, Yu Ying, Kitajima Shuji, Koike Tomonari, Jin Yingji, Morimoto Masatoshi, Hatakeyama Kinta, Asada Yujiro, Watanabe Teruo, Sasaguri Yasuyuki, Watanabe Shigeyuki, Fan Jianglin
Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
Circulation. 2006 Apr 25;113(16):1993-2001. doi: 10.1161/CIRCULATIONAHA.105.596031.
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.
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.
Overexpression of MMP-12 causes accelerated atherosclerosis in Tg rabbits. These results suggest that macrophage-derived MMP-12 participates in the progression of atherosclerosis.
巨噬细胞金属弹性蛋白酶（基质金属蛋白酶[MMP]-12）在动脉粥样硬化病变和动脉瘤中上调；因此，MMP-12活性增加可能在动脉粥样硬化的发病机制中起重要作用。然而，MMP-12在动脉粥样硬化起始和进展中的病理作用尚未明确。
我们比较了MMP-12转基因（Tg）兔与非Tg同窝兔对富含胆固醇饮食诱导的动脉粥样硬化的易感性。通过含有不同量胆固醇的饮食，使兔子在较短时间内维持相对较低水平的高胆固醇血症，或在较长时间内维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水平下，Tg兔和非Tg兔的主动脉粥样硬化病变大小或质量没有显著差异。然而，在较长时间的较高高胆固醇血症水平下，Tg兔的主动脉和冠状动脉中出现了比非Tg兔更广泛的动脉粥样硬化。组织学检查显示，Tg兔的动脉粥样硬化病变中有显著的巨噬细胞浸润，伴有中膜弹性膜的明显破坏，偶尔形成动脉瘤样病变。此外，巨噬细胞来源的MMP-12表达增加与MMP-3表达升高相关，提示MMP-12可能在其他MMP的级联激活中起关键作用，从而在动脉粥样硬化进展过程中加剧细胞外基质降解。
MMP-12的过表达导致Tg兔动脉粥样硬化加速。这些结果表明，巨噬细胞来源的MMP-12参与了动脉粥样硬化的进展。
