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 b y transforming growth factor beta (TGF-beta) in connective tissue cells. CT GF 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 expre ssion in both cardiac fibroblasts and cardiac myocytes. The activity of a C TGF promoter-based reporter construct correlated with endogenous CTGF expre ssion, suggesting that TGF-beta induces CTGF expression most likely by acti vating its promoter. Upregulation of CTGF coincided with an increase in fib ronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF-beta induced CTGF expre ssion and reduced the basal level of CTGF. whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF-bet a induced CTGF expression. Furthermore, we found that both TGF-beta and CTG F mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well wi th concomitant increases in fibronectin, and type I and type III collagen m RNA levels in these animal hearts. Significant upregulation of CTGF was als o detected in human heart samples derived from patients diagnosed with card iac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF-beta signaling in the heart and abnormal expression of thi s gene could be used as a diagnostic marker for cardiac fibrosis. (C) 2000 Academic Press.