巨噬细胞由来的泡沫细胞蓄积是动脉硬化斑块的主要特征。而由巨噬细胞分泌的基质金属蛋白酶对病变部血管壁重塑也起到重要作用。不单促进病变的增长，而且也增加动脉硬化斑块的不稳定性并可引起斑块破裂。哪种MMP是斑块破裂的关键现在还不明确。我们的研究显示，相对于其他巨噬细胞分泌的MMP，在不稳定性病变中MMP-9更为重要。因此推测巨噬细胞由来的MMP-9协调其他的MMPs在斑块破裂形成中起到核心作用，但其机制不详。我们将制作MMP-9的过表达转基因兔。对转基因组兔与对照组附加长期间高胆固醇饮食使其患高脂血症，并继续将其与家族性高脂血症心肌梗死兔模型（WHHL-MI兔）传代，创建MMP-9转基因WHHL-MI兔模型，系统分析各组动物的脂质代谢与病变特征。预期如得到类急性冠脉综合症病变结果或斑块破裂将验证我们的假说。此研究将为动脉硬化及其并发症的防治带来新思路，并建立与临床接近的新型易损斑块实验动物模型。

The accumulation of macrophage-derived foam cells under the intima of large arteries is a hallmark of human and experimental animal atherosclerosis. Macrophages secrete a variety of proteinases that are thought to participate in vascular remodeling of the extracellular matrix (ECM) associated with all stages of atherosclerosis. Increased proteolysis of ECM molecules is probably involved in the initial mononuclear leukocyte emigration from the vascular lumen through the basement membrane into the subendothelial space, the migration and proliferation of medial smooth muscle cells through the elastic laminae in the intima, plaque destabilization, and rupture. But which one of matrix metalloproteinases (MMPs) is the key player in the pathogenesis of atherosclerotic plaque rupture has unknown. Our early results showed that MMP-9 is most important than other MMPs in unstable atherosclerotic lesions; thus we postulated that macrophage-derived MMP-9, in concert with other MMPs, may play a central role in the progression of atherosclerotic lesion and plaque rupture. However, the pathological roles of MMP-9 in lesions have not been defined. First ransgenic (Tg) rabbit overexpressing human MMP-9 will be generated in our laboratory. We can compare the susceptibility of MMP-9 transgenic (Tg) rabbits maintained at higher levels of hypercholesterolemia for longer periods to cholesterol-rich diet–induced atherosclerosis with that of non-Tg littermate rabbits. And we will generate transgenic (Tg) Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHL-MI) rabbits overexpressing human MMP-9 and compared their plasma lipids and aortic atherosclerosis with non-Tg WHHL-MI rabbits. It is also to be expected that Tg rabbits containe prominent macrophage infiltration associated with disruption of fibrotic cap with occasional formation of aneurysm-like or atherothrombotic lesions. This study not only shed fresh light on the functional roles of MMP-9 but also has implications for the notion that specific inhibition of MMP-9 activity may be a candidate therapeutic target for the treatment of atherosclerosis and its complications in the future.