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-beta1 (TGF-beta1) expression, and thereby modulates cardiac fibroblast
collagen metabolism. Experiments were conducted using cardiac fibroblast from neonatal Wistar rats to determine the expression of
TGF-beta1, and the role of U II receptor UT in this process. The functional role of
TGF-beta1 and UT in modulating U II effects on type I, III
collagen mRNA expression and 3H-proline incorporation was also analyzed.
TGF-beta1 gene and
protein expression were consistently identified in quiescent cardiac fibroblasts. U II increased the expression of
TGF-beta1 mRNA and
protein in a time-dependent manner. This effect was UT mediated, because UT antagonist
urantide abolished U II-induced
TGF-beta1 expression. U II-induced increase in type I, III
collagen mRNA expression and 3H-proline incorporation were both inhibited by a specific
TGF-beta1 neutralizing antibody and UT receptor antagonist
urantide. Hence, our results indicate that
TGF-beta1 is upregulated in cardiac fibroblasts by U II via UT and modulates profibrotic effects of U II. These findings provide novel insights into U II-induced cardiac remodeling.