Published online before print June 23, 2005, doi: 10.1161/01.RES.0000174614.74469.83
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Submitted on May 10, 2004
Revised on May 4, 2005
Accepted on June 13, 2005
Endothelin-1, via ETA Receptor and Independently of Transforming Growth Factor-
, Increases the Connective Tissue Growth Factor in Vascular Smooth Muscle Cells
J. Rodriguez-Vita ;
From the Vascular and Renal Research Laboratory, Fundación Jiménez Diaz, Universidad Autónoma Madrid, Spain
* To whom correspondence should be addressed. E-mail: mruizo{at}fjd.es.
Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardiovascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in vascular fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and collagen expression in ET-1-treated cells, showing that CTGF participates in ET-1-induced ECM accumulation. The ETA, but not ETB, antagonist diminished ET-1-induced CTGF gene and production. Several intracellular signals elicited by ET-1, via ETA receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-
- and angiotensin (Ang) II-induced fibrosis. In VSMCs, ET-1 did not upregulate TGF- gene or protein. The presence of neutralizing transforming growth factor (TGF)- antibody did not modify ET-1-induced CTGF production, showing a TGF--independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ETA antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF- and through the activation of several intracellular signals via ETA receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in vascular diseases.
Key words: endothelin-1 • connective tissue growth factor • signal transduction • vascular smooth muscle cells • extracellular matrix
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