Rapidly accumulating evidence points to the matrix metalloproteinases (MMPs) as major molecular mediators of arterial diseases. Findings from human pathological specimens, animals, and cell and molecular biology implicate matrix metalloproteinases in all stages of atherosclerosis including lesion initiation and progression and ultimately in plaque complication and triggering of thrombosis. The complex interactions within the proteolytic cascade allow multiple levels of control over these functions. This review weighs the evidence for the role of MMPs in arterial biology with particular reference to their activation in the atherosclerotic plaque.
Background-Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease.Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheromarelated cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity. Methods and Results-Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (nϭ7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1, TNF-␣, or IFN-␥ but released it when stimulated by CD40 ligand, a cytokine found in atheroma. Conclusions-These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.
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