Published online before print March 1, 2004, doi: 10.1161/01.CIR.0000121728.14930.DE
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(Circulation. 2004;109:1408-1414.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
Loss of Matrix Metalloproteinase-9 or Matrix Metalloproteinase-12 Protects Apolipoprotein E–Deficient Mice Against Atherosclerotic Media Destruction but Differentially Affects Plaque Growth
From the Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Leuven, Belgium (A.L., A.M., K.M., D.C., P.C., L.M.), and Cardiovascular Research Institute, University of Maastricht, Maastricht, the Netherlands (E.L.).
Correspondence to Peter Carmeliet, MD, PhD, Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium. E-mail peter.carmeliet{at}med.kuleuven.ac.be
Received September 13, 2002; de novo received July 22, 2003; revision received November 5, 2003; accepted November 13, 2003.
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.
Key Words: atherosclerosis • aneurysm • metalloproteinases • collagen • hypercholesterolemia
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