Matrix metalloproteinases (MMP) have been identified in vulnerable areas of atherosclerotic plaques and may contribute to plaque instability through extracellular matrix degradation. Human metalloelastase (MMP-12) is a macrophage-specific MMP with broad substrate specificity and is capable of degrading proteins found in the extracellular matrix of atheromas. Despite its potential importance, little is known about the regulation of MMP-12 expression in the context of atherosclerosis. In this study, we report that in human peripheral bloodderived macrophages, MMP-12 mRNA was markedly upregulated by several pro-atherosclerotic cytokines and growth factors including interleukin-1, tumor necrosis factor-, macrophage colony-stimulating factor, vascular endothelial growth factor, and platelet-derived growth factor-BB. In contrast, the pleiotropic anti-inflammatory growth factor transforming growth factor-1 (TGF-1) inhibited cytokine-mediated induction of MMP-12 mRNA, protein, and enzymatic activity. Analyses of MMP-12 promoter through transient transfections and electrophoretic mobility shift assays indicated that both its induction by cytokines and its inhibition by TGF-1 depended on signaling through an AP-1 site at 81 base pairs. Moreover, the inhibitory effect of TGF-1 on MMP-12 was dependent on Smad3. Taken together, MMP-12 is induced by several factors implicated in atherosclerosis. The inhibition of MMP-12 expression by TGF-1 suggests that TGF-1, acting via Smad3, may promote plaque stability.

Atherosclerosis leads to myocardial infarction and stroke and is the principal cause of death in Western societies (1). Advanced atherosclerotic lesions consist of a fibrous cap and a lipid core (2, 3). Lesions with a thin fibrous cap overlying a large lipid-rich core are more vulnerable to coronary plaque rupture, a key pathophysiologic event often resulting in myo-