CTGF Expression is Induced by TGF- β in Cardiac Fibroblasts and Cardiac Myocytes: a Potential Role in Heart Fibrosis

• Published in: Journal of molecular and cellular cardiology Vol. 32; no. 10; pp. 1805 - 1819
• Main Authors: Chen, Michelle M, Lam, Andrew, Abraham, Judith A, Schreiner, George F, Joly, Alison H
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2000
• Subjects: Adult; Aged; Animals; Animals, Newborn; Biomarkers; Blotting, Northern; Cells, Cultured; Colforsin - metabolism; Collagen - metabolism; Connective Tissue Growth Factor; CTGF; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Extracellular matrix; Extracellular Matrix - metabolism; Female; Fibroblasts - metabolism; Fibronectins - metabolism; Fibrosis; Flavonoids - pharmacology; Genes, Reporter; Growth Substances - biosynthesis; Growth Substances - genetics; Heart Diseases - metabolism; Heart Ventricles - metabolism; Humans; Immediate-Early Proteins - biosynthesis; Immediate-Early Proteins - genetics; Intercellular Signaling Peptides and Proteins; Ischemic heart disease; Luciferases - metabolism; Male; MAP Kinase Signaling System; Middle Aged; Myocardial infarction; Myocardial Infarction - metabolism; Myocardium - metabolism; Plasminogen Activator Inhibitor 1 - metabolism; Promoter Regions, Genetic; Quantitative real-time PCR; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal transduction pathway; Time Factors; Tissue Distribution; Transforming Growth Factor beta - metabolism; Up-Regulation; Myocardial infarction; Ischemic heart disease; Quantitative real-time PCR; Extracellular matrix; Signal transduction pathway; CTGF
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1006/jmcc.2000.1215

Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF- β) 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- β 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- β 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- β 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- β induced CTGF expression. Furthermore, we found that both TGF- β 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- β signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis.