Persistence of Atherosclerotic Plaque but Reduced Aneurysm Formation in Mice With Stromelysin-1 (MMP-3) Gene Inactivation

Abstract

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.