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Matrix metalloproteinase‐12 gene expression in human vascular smooth muscle cells
Author(s) -
Wu Lihua,
Tanimoto Akihide,
Murata Yoshitaka,
Sasaguri Takakazu,
Fan Jianglin,
Sasaguri Yasuyuki,
Watanabe Teruo
Publication year - 2003
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1046/j.1365-2443.2003.00628.x
Subject(s) - biology , vascular smooth muscle , wortmannin , microbiology and biotechnology , phosphatidylinositol , electrophoretic mobility shift assay , matrix metalloproteinase , gene expression , gene , kinase , biochemistry , endocrinology , smooth muscle
Background: Matrix metalloproteinases (MMPs) play an important role in smooth muscle cell (SMC) migration and proliferation during vascular remodelling. To investigate the expression of MMP‐12 by SMCs, we examined the protein secretion and mRNA expression of MMP‐12 by cultured medial SMCs and intimal SMCs derived from human aortic atherosclerotic lesions. To further elucidate the molecular mechanism for MMP‐12 expression in SMCs, we determined the sequence requirements for MMP‐12 gene transcriptional activity. Results: Cultured medial SMCs and intimal SMCs showed substantial MMP‐12 expression at both the protein and mRNA levels. A series of 5′‐deletion and site‐directed mutants of the human MMP‐12 promoter demonstrated that an AP‐1 site spanning −81 to −75 bp was critical for the MMP‐12 promoter activity in SMCs. An electrophoretic mobility shift assay confirmed the AP‐1 binding activity in SMCs and showed that the protein bound to the AP‐1 site consisted predominantly of c‐Jun, JunD and Fra‐1. Two structurally different inhibitors of phosphatidylinositol 3‐kinase, wortmannin and LY294002, inhibited MMP‐12 transcriptional activity and AP‐1 binding. Conclusion: These results indicated the expression of MMP‐12 in vascular SMCs and showed that the MMP‐12 gene expression was dependent on the AP‐1 binding activity. Phosphatidylinositol 3‐kinase signalling may be involved in MMP‐12 transcriptional activation through AP‐1 binding activity.