It is now well established that
urotensin-II (UII) levels are increased in several
cardiovascular diseases. We previously demonstrated that UII and the UII receptor (UT)
protein levels are significantly increased in the hearts of both humans and rats with
congestive heart failure (CHF). We have also recently demonstrated that UII blockade, with a selective UII antagonist, improves heart function in a rat model of ischemic CHF. Here, we evaluated the attenuation of cardiac remodeling associated with UII antagonism in the same rat model of ischemic CHF. Animals were administered a specific UT receptor antagonist,
SB-611812 (30 mg/kg/day, gavage), or vehicle 30 min prior to coronary artery
ligation followed by daily treatment for 8 weeks. Myocardial interstitial
fibrosis was analyzed by Masson's trichrome and
picrosirius red staining. RT-PCR analysis was utilized for
mRNA expression studies. We used Western blotting to assess levels of
collagen types I and III. Mitogenic activity of UII on cultured neonatal cardiac fibroblasts was also evaluated. Following coronary
ligation,
SB-611812 significantly attenuated both myocardial and endocardial interstitial
fibrosis, and reduced
collagen type I:III ratio (P<0.01). UII induced proliferation of cardiac fibroblasts and this mitogenic effect was significantly inhibited with 1 microM of SB-611218 (P<0.05). We demonstrate here that selective blockade of UT reduces diastolic dysfunction by decreasing myocardial
fibrosis post-coronary
ligation in vivo, and inhibits UII-mediated fibroblast proliferation in vitro.