Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth
Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth
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DOI：
10.1161/01.cir.0000121728.14930.de
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发表时间：
2004-03-23
期刊：
影响因子：
37.8
通讯作者：
Moons, L
中科院分区：
文献类型：
--
作者：
Luttun, A;Lutgens, E;Moons, L
背景-流行病学和组织学证据表明基质金属蛋白酶（MMP）家族的蛋白酶与动脉粥样硬化和动脉瘤形成有关。我们之前指出了尿激酶型纤溶酶原激活剂在MMPs蛋白水解激活的动脉粥样硬化介质破坏中的作用。然而，特异性MMPs，如MMP-9和MMP-12，在动脉粥样硬化中的作用仍不明确。方法与结果：在动脉粥样硬化易发的载脂蛋白E缺乏背景下，将MMP-9或MMP-12缺陷小鼠杂交，并饲喂富含胆固醇的饮食。小鼠分别在15周或25周时被杀死，以研究中期和晚期病变。MMP-9的缺失减少了整个主动脉的动脉粥样硬化负担，损害了巨噬细胞的浸润和胶原沉积，而MMP-12的缺乏不影响病变的生长。MMP-9或MMP-12缺乏对动脉粥样硬化介质中跨内侧弹性蛋白降解和扩张具有显著的保护作用。结论：这项研究首次提供了直接的遗传证据，证明MMP-9而非MMP-12参与了动脉粥样硬化斑块的生长。此外，MMP-9或MMP-12的缺乏可以保护载脂蛋白E -缺陷小鼠免受动脉粥样硬化介质破坏和扩张，这一机制暗示了这些MMPs参与动脉瘤形成。
Background - Epidemiological and histological evidence implicates proteinases of the matrix metalloproteinase (MMP) family in atherosclerosis and aneurysm formation. We previously indicated a role for urokinase-type plasminogen activator in atherosclerotic media destruction by proteolytic activation of MMPs. However, the role of specific MMPs, such as MMP-9 and MMP-12, in atherosclerosis remains undefined.Methods and Results - MMP-9 - or MMP-12 - deficient mice were crossed in the atherosclerosis-prone apolipoprotein E - deficient background and fed a cholesterol-rich diet. Mice were killed at 15 or 25 weeks of diet to study intermediate and advanced lesions, respectively. Loss of MMP-9 reduced atherosclerotic burden throughout the aorta and impaired macrophage infiltration and collagen deposition, while MMP-12 deficiency did not affect lesion growth. MMP-9 or MMP-12 deficiency conferred significant protection against transmedial elastin degradation and ectasia in the atherosclerotic media.Conclusions - This study is the first to provide direct genetic evidence for a significant involvement of MMP-9, but not of MMP-12, in atherosclerotic plaque growth. In addition, deficiency of MMP-9 or MMP-12 protected apolipoprotein E - deficient mice against atherosclerotic media destruction and ectasia, mechanisms that implicate the involvement of these MMPs in aneurysm formation.