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 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 MNIP activity, as a result of TIMP-1 deficiency, contributes to a reduction of atherosclerotic plaque size but prornotes aneurysm formation.