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

Abstract

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.