Urotensin-II (U-II), the most potent mammalian
vasoconstrictor identified, and its receptor, UT, exhibits increased expression in cardiac tissue and plasma in
congestive heart failure (CHF) patients. Cardiomyocyte
hypertrophy is primarily responsible for increased myocardial mass associated with cardiac injury. Neurohumoral factors such as
angiotensin-II,
endothelin-1,
catecholamines, and inflammatory
cytokines are thought to mediate this response. U-II shares similar
biological activities with other hypertrophic G(q)-coupled receptor
ligands such as
angiotensin-II and
endothelin-1, but a role for U-II in cardiomyocyte
hypertrophy has not been characterized. The hypothesis of the current study was that U-II, acting through its G(q)-coupled receptor UT plays a hypertrophic role in cardiac hypertrophic remodeling. We report that adenoviral upregulation of the UT receptor "unmasked" U-II-induced
hypertrophy in H9c2 cardiomyocytes, with a threshold response of 202+/-8 binding sites/cell. U-II was equally as efficacious as
phenylephrine in inducing
hypertrophy, measured by a reporter assay (EC(50) 0.7+/-0.2 nM) and [(3)H]-
leucine incorporation (EC(50) 150+/-40 nM). A competitive peptidic UT receptor antagonist,
BIM-23127, inhibited U-II-induced
hypertrophy ( K(B) 34+/-6 nM). U-II did not affect cell proliferation or apoptosis, indicating that U-II is more hypertrophic than apoptotic or hyperplastic in cardiomyocytes. U-II (10 nM) stimulated
interleukin-6 release in UT-expressing cardiomyocytes (4.6-fold at 6 h). Finally, in a rat
heart failure model, cardiac ventricular
mRNA expression of U-II, UT
receptor, interleukin-6, and interleukin-1-beta is increased time-dependently following myocardial injury. These results indicate that U-II might play a role in cardiac remodeling associated with CHF by stimulation of cardiomyocyte
hypertrophy via UT, and through upregulation of inflammatory
cytokines. As such, UT antagonism may represent a novel therapeutic target for the clinical management of
heart failure.