Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques - Evidence for activation by proinflammatory mediators

Background-Matrix metalloproteinases (MMPs) are expressed in atheroscleroti c plaques, where in their active form, they may contribute to vascular remo deling and plaque disruption. In this study, we tested the hypothesis that membrane type 1 MMP (MT1-MMP), a novel transmembrane MMP that activates pro -MMP-2 (gelatinase A), is expressed in human atherosclerotic plaques and th at its expression is regulated by proinflammatory molecules. Methods and Results--MT1-MMP expression was examined in normal and atherosc lerotic human arteries by immunocytochemistry with specific antibodies. MT1 -MMP expression in human saphenous vein-derived smooth muscle cells (SMCs) maintained in tissue culture was determined under basal conditions and in r esponse to proinflammatory molecules (interleukin [IL]-1 alpha, tumor necro sis factor [TNF]-alpha, and oxidized LDL [ox-LDL]) by use of Northern blot and ribonuclease protection assays for mRNA, Western blot and immunoprecipi tation for protein, and gelatin zymography for catalytic activity. Medial S MCs of normal vessel wall expressed MT1-MMP, In atherosclerotic arteries, M T1-MMP expression was noted within the complex atheroma colocalizing with S MCs and macrophages (M phi). Cultured SMCs constitutively expressed MT1-MMP mRNA and protein, which increased 2- to 4-fold over control in a time-depe ndent manner within 4 to 8 hours of exposure to IL-1 alpha, TNF-alpha, and ox-LDL (thiobarbituric acid-reactive substances, 13.4 nmol/mg LDL protein), whereas native LDL had no effect. Flow cytometry revealed MT1-MMP expressi on by human monocyte-derived M phi, which increased 3.8-fold over baseline within 6 hours after exposure to 10 ng/mL TNF-alpha. Conclusions-This study demonstrates that MT1-MMP, an activator of pro-MMP-2 , is expressed by SMCs and M phi in human atherosclerotic plaques. Furtherm ore, proinflammatory molecules upregulate MT1-MMP expression in vascular SM Cs and M phi. Thus, activation of SMCs and M phi by proinflammatory molecul es may influence extracellular matrix remodeling in atherosclerosis by regu lating MT1-MMP expression.