Induction of the MMP-14 Gene in Macrophages of the Atherosclerotic Plaque

Based on epidemiological and pathological studies, it is becoming increasingly clear that matrix metalloproteinases (MMPs) play an important role in the pathogenesis of atherosclerosis by participating in vascular remodeling, smooth muscle cell migration, and plaque disruption. MMP-14, because of its unique ability to cause pericellular degradation, its broad substrate specificity, its synthesis in an active form, and its ability to activate other matrix metalloproteinases, is recognized as a prominent member of this family. MMP-14 is detected at high levels in the atherosclerotic plaque. To understand the induction mechanism of MMP-14 under atherogenic conditions, we examined its expression pattern in response to oxidized low-density lipoproteins (ox-LDLs) that are believed to play an important role in atherogenesis. We report that in macrophages, ox-LDLs markedly elevate the levels of MMP-14 mRNA and protein. The cis -acting elements supporting this increase were identified to be present within −213 and −1 nucleotides of the MMP-14 promoter. DNase I protection assay revealed, within this region, two major elements, of which one serves as the DNA-binding site for SAF-1 transcription factor. Increased binding of SAF-1 to the MMP-14 promoter correlated with the transcriptional upregulation of MMP-14 gene. Furthermore, induction of endogenous MMP-14 gene, MMP-14 promoter driven reporter gene expression and MMP-2 processing activity during overexpression of SAF-1 and coexpression of SAF-1 and MMP-14 in the macrophages present in the atherosclerotic plaque implicate SAF-1 as a key regulator of MMP-14 gene induction in macrophage cells.