CTGF expression is induced by TGF- beta in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis.
Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF- beta) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix; however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF- beta is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF- beta induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF- beta induced CTGF expression and reduced the basal level of CTGF, whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF- beta induced CTGF expression. Furthermore, we found that both TGF- beta and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF- beta signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis.
Chen
M M
MM
Scios Inc, 820 West Maude Ave, Sunnyvale, CA 94086, USA. chenm@sciosinc.com
Lam
A
A
Abraham
J A
JA
Schreiner
G F
GF
Joly
A H
AH
D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers; D015152:Blotting, Northern; D002478:Cells, Cultured; D005576:Colforsin / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D005419:Flavonoids / Q000494:pharmacology; D017930:Genes, Reporter; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D006331:Heart Diseases / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D015415:Biomarkers; C526317:CCN2 protein, human; C526316:CCN2 protein, rat; D005353:Fibronectins; D005419:Flavonoids; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D005576:Colforsin; D003094:Collagen; D008156:Luciferases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one