Lesional overexpression of matrix metalloproteinase-9 promotes intraplaque hemorrhage in advanced lesions but not at earlier stages of atherogenesis
Lesional overexpression of matrix metalloproteinase-9 promotes intraplaque hemorrhage in advanced lesions but not at earlier stages of atherogenesis
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DOI：
10.1161/01.atv.0000197795.56960.64
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发表时间：
2006-02-01
影响因子：
8.7
通讯作者：
Biessen, EAL
中科院分区：
文献类型：
--
作者：
de Nooijer, R;Verkleij, CJN;Biessen, EAL
基质金属蛋白酶-9（MMP-9）参与动脉粥样硬化，在不稳定斑块中发现MMP-9活性升高，提示其在斑块破裂中起关键作用。本研究旨在评估MMP-9对载脂蛋白E缺陷小鼠斑块稳定性的影响，在不同阶段的斑块progression.Methods和Results -动脉粥样硬化病变引起颈动脉血管周围衣领放置。MMP-9过度表达的中期或晚期斑块的影响腔内孵育的腺病毒（Ad.MMP-9）。将一个亚组与Ad.TIMP-1共孵育。模拟病毒作为对照。对斑块进行组织学分析。在中度病变中，MMP-9过度表达诱导向外重塑，如中膜大小增加30%所示（p=0.03）。在中度和晚期病变中，易损斑块形态的患病率趋于增加。MMP-9治疗的病变有一半显示斑块内出血，而对照组和Ad. MMP-9/Ad.TIMP-1组分别为8%和16%（p=0.007）。与新生血管共定位可能指向新血管生成作为intraperectivehemorrhage.Conclusion的来源-这些数据显示了不同的影响MMP-9在斑块进展的各个阶段，并建议病变靶向MMP-9抑制可能是一个有价值的治疗方式，在稳定先进的斑块，但不是在病变进展的早期阶段。
Background - Matrix metalloproteinase-9 (MMP-9) is involved in atherosclerosis and elevated MMP-9 activity has been found in unstable plaques, suggesting a crucial role in plaque rupture. This study aims to assess the effect of MMP-9 on plaque stability in apolipoprotein E-deficient mice at different stages of plaque progression.Methods and Results - Atherosclerotic lesions were elicited in carotid arteries by perivascular collar placement. MMP-9 overexpression in intermediate or advanced plaques was effected by intraluminal incubation with an adenovirus (Ad.MMP-9). A subset was coincubated with Ad.TIMP-1. Mock virus served as a control. Plaques were analyzed histologically. In intermediate lesions, MMP-9 overexpression induced outward remodeling, as shown by a 30% increase in media size (p=0.03). In both intermediate and advanced lesions, prevalence of vulnerable plaque morphology tended to be increased. Half of MMP-9 - treated lesions displayed intraplaque hemorrhage, whereas in controls and the Ad. MMP-9/Ad.TIMP-1 group this was 8% and 16%, respectively (p=0.007). Colocalization with neovessels may point to neo-angiogenesis as a source for intraplaque hemorrhage.Conclusion - These data show a differential effect of MMP-9 at various stages of plaque progression and suggest that lesion-targeted MMP-9 inhibition might be a valuable therapeutic modality in stabilizing advanced plaques, but not at earlier stages of lesion progression.