Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1440-1445
doi: 10.1161/hq0901.097004
doi: 10.1161/hq0901.097004
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Persistence of Atherosclerotic Plaque but Reduced Aneurysm Formation in Mice With Stromelysin-1 (MMP-3) Gene Inactivation
From the Center for Molecular and Vascular Biology (J.S., D.C., H.R.L.), University of Leuven, Leuven, Belgium, and the Cardiovascular Biology Research Program (F.L.), Oklahoma Medical Research Foundation, Oklahoma City, Okla..
Correspondence to H.R. Lijnen, PhD, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O & N, Herestraat 49, B-3000 Leuven, Belgium. E-mail roger.lijnen{at}med.kuleuven.ac.be
Abstract—— To investigate a potential role for stromelysin-1 (MMP-3) in the development and progression of atherosclerotic lesions and aneurysm formation, mice with a deficiency of apolipoprotein E (ApoE-/-:MMP-3+/+)) or with a combined deficiency of apoE and MMP-3 (ApoE-/-:MMP-3-/-) were kept on a cholesterol-rich diet for 30 weeks. Atherosclerotic lesions throughout the thoracic aorta were significantly larger in ApoE-/-:MMP-3-/- than in ApoE-/-:MMP-3+/+ mice (P<0.05) and contained more fibrillar collagen (P<0.01). Aneurysms in the thoracic and abdominal aortas were less frequent in ApoE-/-:MMP-3-/- than in ApoE-/-:MMP-3+/+ mice (8.5±1.7% vs 14±2.1% of sections, mean±SD, P<0.01). Immunocytochemistry revealed enhanced accumulation of macrophages in atherosclerotic lesions of ApoE-/-:MMP-3+/+ mice (P<0.01) and expression of urokinase-type plasminogen activator (u-PA) and MMP-3 colocalizing with macrophages. Zymography confirmed the presence of u-PA and MMP-3 activity in extracts of atherosclerotic aortas. These data suggest that plasmin, generated by macrophage-secreted u-PA, activates pro-MMP-3 produced by accumulated macrophages. MMP-3 activity may then contribute to a reduction of plaque size, possibly by degradation of matrix components, and promote aneurysm formation by degradation of the elastica lamina.
Key Words: matrix metalloproteinases • stromelysin-1 • apolipoprotein E • atherosclerosis • aneurysm
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