Increased MMP-2 expression in connective tissue growth factor over-expression vascular smooth muscle cells.
Connective tissue growth factor (CTGF) is abundantly expressed in the vascular smooth muscle cells (VSMC) of atherosclerotic lesions but not in normal vessels. CTGF is able to promote VSMC proliferation and migration and influences the composition of extracellular matrix. The mechanisms for controlling these events remain unclear. We studied the effects of CTGF on matrix metalloproteinases (MMPs) by introducing a CTGF over-expression construct into VSMC. We found that the over-expression of CTGF significantly increased the activity of MMP-2 in VSMC conditioned medium. MMP-2 activity was similarly increased by exogenous CTGF treatment, and this effect could be blocked by an anti-CTGF antibody. We also showed that the increased MMP-2 activity was due to an increase in MMP-2 mRNA levels in VSMC. We further studied the mechanisms involved in the regulation of MMP-2 mRNA levels and found that the AP-2 transcription factor is responsible for most of the CTGF-induced MMP-2 transcription. Because MMP-2 is an important factor directly involved in controlling cell movement and the turnover of extracellular matrix, our study may provide a mechanism for CTGF-promoted VSMC migration.
Fan
Wen-Hua
WH
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. wenhuafan@hms.harvard.edu
Karnovsky
Morris J
MJ
D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006133:Growth Substances / Q000096:biosynthesis*; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D036341:Intercellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000201:enzymology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
C526316:CCN2 protein, rat; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D019716:Tissue Inhibitor of Metalloproteinase-2; D055513:Connective Tissue Growth Factor; D020778:Matrix Metalloproteinase 2