Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth

被引:256
作者
Luttun, A
Lutgens, E
Manderveld, A
Maris, K
Collen, D
Carmeliet, P
Moons, L
机构
[1] Katholieke Univ Leuven VIB, Ctr Transgene Technol & Gene Therapy, B-3000 Leuven, Belgium
[2] Univ Maastricht, Cardiovasc Res Inst, Maastricht, Netherlands
关键词
atherosclerosis; aneurysm; metalloproteinases; collagen; hypercholesterolemia;
D O I
10.1161/01.CIR.0000121728.14930.DE
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1408 / 1414
页数:7
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