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, 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.
Recchia
Anna Grazia
AG
Department of Pharmaco-Biology, Cell Biology, University of Calabria, 87036 Rende (CS), Italy.
Filice
Elisabetta
E
Pellegrino
Daniela
D
Dobrina
Aldo
A
Cerra
Maria Carmela
MC
Maggiolini
Marcello
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000628:therapy; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis*; D058575:Decorin; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D009124:Muscle Proteins / Q000096:biosynthesis*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011509:Proteoglycans / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects
C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; C546878:DCN protein, human; C546879:Dcn protein, mouse; C546880:Dcn protein, rat; D058575:Decorin; D019332:Endothelin-1; D016326:Extracellular Matrix Proteins; D009124:Muscle Proteins; D011509:Proteoglycans; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D055513:Connective Tissue Growth Factor; C483803:Egfr protein, rat; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases