Matrix metalloproteinases: are they antiatherogenic but proaneurysmal?

Abstract

The matrix metalloproteinases (MMPs) are a family of enzymes (25 identified to date) that have in common the ability to degrade many molecules of the extracellular matrix. MMP activity can be inhibited by the endogenous tissue inhibitors of metalloproteinases (TIMPs 1 through 4), and the net proteolytic activity within a tissue is a function of the balance of MMPs/TIMPs.1 Numerous studies have shown that MMPs and TIMPs are expressed during vascular remodeling in the pathological conditions of atherosclerosis, restenosis, and aneurysm formation.2 Despite this burgeoning knowledge, we are still hampered by an incomplete understanding of the scope and the consequences of MMP/TIMP involvement in the pathogenesis of vascular disease. In atherosclerosis and restenosis, MMPs are produced by the major cell types inhabiting the plaque, vascular smooth muscle cells (SMCs), and leukocytes of the monocyte/macrophage and lymphocytic lineages. MMP-1, -2, -3, -9, -12, and -13 have been detected in plaques, along with the TIMP-1, -2, and -4.2 MMPs produced by SMCs clear a path for migration from media to intima by digesting the extracellular matrix, and SMC migration can be inhibited by administration of nonselective MMP inhibitors3–5⇓⇓ or transfection of the genes for TIMP-1 or TIMP-2 into the injured vessel wall.6,7⇓ Macrophages produce abundant amounts of MMPs, which are used to invade through the endothelium and into the atherosclerotic plaque.8 MMPs are colocalized with …