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


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.
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Leuven, Belgium.
Aernout
A
Luttun
Esther
E
Lutgens
Ann
A
Manderveld
Katleen
K
Maris
Désiré
D
Collen
Peter
P
Carmeliet
Lieve
L
Moons
D000818:Animals; D001018:Aortic Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D004036:Diet, Atherogenic; D004108:Dilatation, Pathologic; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D006937:Hypercholesterolemia / Q000150:complications; D008264:Macrophages / Q000473:pathology; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017540:Tunica Media / Q000473:pathology*
D001057:Apolipoproteins E; D003094:Collagen; D004549:Elastin; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12