期刊
CIRCULATION RESEARCH
卷 95, 期 11, 页码 1082-1090出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000150046.48115.80
关键词
MMP-14; SAF-1; atherosclerotic plaques; oxidized LDL; macrophages
资金
- NHLBI NIH HHS [HL36088, HL52490] Funding Source: Medline
- NIAMS NIH HHS [AR48762, AR47074] Funding Source: Medline
- NIDDK NIH HHS [DK49205] Funding Source: Medline
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.
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