Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation.
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.
Silence
J
J
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
Lupu
F
F
Collen
D
D
Lijnen
H R
HR
D000783:Aneurysm / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004036:Diet, Atherogenic; D005260:Female; D005838:Genotype; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008264:Macrophages / Q000737:chemistry; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D014568:Urokinase-Type Plasminogen Activator / Q000276:immunology / Q000378:metabolism
D000943:Antigens, Differentiation; D001057:Apolipoproteins E; C036763:monocyte-macrophage differentiation antigen; D014568:Urokinase-Type Plasminogen Activator; D019278:Matrix Metalloproteinase 3