The involvement of transforming growth factor-β1 secretion in Urotensin II-induced collagen synthesis in neonatal cardiac fibroblasts

As the most potent vasoconstrictor in mammals, urotensin II (U II) has recently been demonstrated to play an important role in adverse cardiac remodeling and fibrosis. However, the mechanisms of U II-induced myocardial fibrosis remain to be clarified. We postulated that U II alters transforming growth factor-beta 1 (TGF-beta 1) expression, and thereby modulates cardiac fibroblast collagen metabolism. Experiments were conducted using cardiac fibroblast from neonatal Wistar rats to determine the expression of TGF-beta 1, and the role of U II receptor UT in this process. The functional role of TGF-beta 1 and UT in modulating U II effects on type I, III collagen mRNA expression and H-3-proline incorporation was also analyzed. TGF-beta 1 gene and protein expression were consistently identified in quiescent cardiac fibroblasts. U II increased the expression of TGF-beta 3 I mRNA and protein in a time-dependent manner. This effect was UT mediated, because UT antagonist urantide abolished U II-induced TGF-beta 1 expression. U II-induced increase in type I, III collagen mRNA expression and H-3-proline incorporation were both inhibited by a specific TGF-beta 1 neutralizing antibody and UT receptor antagonist urantide. Hence, our results indicate that TGF=beta 1 is upregulated in cardiac fibroblasts by U 11 via UT and modulates profibrotic effects of U II. These findings provide novel insights into U II-induced cardiac remodeling. (c) 2006 Elsevier B.V. All rights reserved.