ENDOTHELIN-1 INDUCES CONNECTIVE TISSUE GROWTH FACTOR EXPRESSION IN CARDIOMYOCYTES

Endothelin (ET)-1 is a vasoconstrictor involved in cardiovascular diseases. Connective tissue growth factor/CCN2 (CTGF) is a fibrotic mediator overexpressed in human atherosclerotic lesions, myocardial infarction,and hypertension. In different cell types CTGF regulates cell proliferation/apoptosis, migration, andextracellular matrix (ECM) accumulation and plays important roles in angiogenesis, chondrogenesis,osteogenesis, tissue repair, cancer and fibrosis. In the present study, we investigated the ET-1 signaling whichtriggers CTGF expression in cultured adult mouse atrial-muscle HL-1 cells used as a model system. ET-1activated the CTGF promoter and induced CTGF expression at both mRNA and protein levels. Real-time PCRanalysis revealed CTGF induction also in isolated rat heart preparations perfused with ET-1. Severalintracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor (EGFR)contributed to the up-regulation of CTGF, including ERK activation and induction of the AP-1 components cfosand c-jun, as also evaluated by ChIP analysis. Moreover, in cells treated with ET-1 the expression of ECMcomponent decorin was abolished by CTGF silencing, indicating that CTGF is involved in ET-1 induced ECMaccumulation not only in a direct manner but also through downstream effectors. Collectively, our dataindicate that CTGF could be a mediator of the profibrotic effects of ET-1 in cardiomyocytes. CTGF inhibitorsshould be considered in setting a comprehensive pharmacological approach towards ET-1 inducedcardiovascular diseases.