Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene.
Development and progression of atherosclerotic lesions and aneurysm formation were investigated in mice with single or combined deficiency of apolipoprotein E (ApoE) and tissue inhibitor of metalloproteinase-1 (TIMP-1) kept on a cholesterol-rich diet for 30 weeks. Atherosclerotic lesions throughout the thoracic aorta were significantly (P<0.001) larger in mice wild-type for TIMP-1 (ApoE-/-:TIMP-1+/+) than in mice deficient in TIMP-1 (ApoE-/-:TIMP-1-/-). Aneurysms in the thoracic and abdominal aortas were less frequent in ApoE-/-:TIMP-1+/+ mice than in ApoE-/-:TIMP-1-/- mice (11+/-3.0 versus 23+/-5.1 aneurysms per 100 sections analyzed, mean+/-SD, P<0.001). Immunocytochemistry revealed enhanced accumulation of Oil red O-stained lipids, colocalizing with macrophages in atherosclerotic lesions of ApoE-/-:TIMP-1-/- mice (P<0.05). In situ zymography using a casein substrate showed enhanced lysis in plaques of ApoE-/-:TIMP-1-/- mice as compared with ApoE-/-:TIMP-1+/+ mice (P<0.01). MMP activity was most pronounced at sites where degradation of the elastic lamina occurred. These data suggest that enhanced MMP activity, as a result of TIMP-1 deficiency, contributes to a reduction of atherosclerotic plaque size but promotes aneurysm formation.
Silence
J
J
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
Collen
D
D
Lijnen
H R
HR
D000818:Animals; D001011:Aorta / Q000473:pathology; D001014:Aortic Aneurysm / Q000209:etiology*; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004036:Diet, Atherogenic; D018450:Disease Progression; D005260:Female; D008055:Lipids / Q000032:analysis; D008264:Macrophages; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000502:physiology*
D001057:Apolipoproteins E; D008055:Lipids; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases