Endothelin-1 induces connective tissue growth factor expression in cardiomyocytes

• Published in: Journal of molecular and cellular cardiology 2009-03, Vol.46 (3), p.352-359
• Main Authors: Recchia, Anna Grazia, Filice, Elisabetta, Pellegrino, Daniela, Dobrina, Aldo, Cerra, Maria Carmela, Maggiolini, Marcello
• Format: Article
• Language: English
• Subjects: Animals; AP-1; Apoptosis - drug effects; Cardiomyocytes; Cardiovascular; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - therapy; Cell Line; Cell Movement - drug effects; Cell Proliferation - drug effects; Connective tissue growth factor; Connective Tissue Growth Factor - biosynthesis; Decorin; Endothelin-1; Endothelin-1 - metabolism; Endothelin-1 - pharmacology; Enzyme Activation - drug effects; ErbB Receptors - metabolism; Extracellular Matrix Proteins - biosynthesis; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation; Humans; Male; Mice; Models, Biological; Muscle Proteins - biosynthesis; Myocytes, Cardiac - metabolism; Proteoglycans - biosynthesis; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Rats; Rats, Wistar; Receptors, Endothelin - agonists; Receptors, Endothelin - metabolism; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - biosynthesis; Signal transduction; Signal Transduction - drug effects
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2008.11.017

Abstract 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, and extracellular 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 which triggers CTGF expression in cultured adult mouse atrial-muscle HL-1 cells used as a model system. ET-1 activated the CTGF promoter and induced CTGF expression at both mRNA and protein levels. Real-time PCR analysis revealed CTGF induction also in isolated rat heart preparations perfused with ET-1. Several intracellular 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 c- fos and c- jun , as also evaluated by ChIP analysis. Moreover, in cells treated with ET-1 the expression of ECM component decorin was abolished by CTGF silencing, indicating that CTGF is involved in ET-1 induced ECM accumulation not only in a direct manner but also through downstream effectors. Collectively, our data indicate that CTGF could be a mediator of the profibrotic effects of ET-1 in cardiomyocytes. CTGF inhibitors should be considered in setting a comprehensive pharmacological approach towards ET-1 induced cardiovascular diseases.