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Reduced Atherosclerotic Plaque but Enhanced Aneurysm Formation in Mice With Inactivation of the Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Gene

From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.

Correspondence to H.R. Lijnen, 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

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.

Key Words: matrix metalloproteinases • tissue inhibitor of metalloproteinase-1 • apolipoprotein E • atherosclerosis • aneurysm

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