Urotensin-II receptor blockade with SB-611812 attenuates cardiac remodeling in experimental ischemic heart disease.
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.
Bousette
Nicolas
N
Division of Cardiology, Montreal General Hospital, McGill University Health Center, Suite L3-109, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada.
Pottinger
Julia
J
Ramli
Wisam
W
Ohlstein
Eliot H
EH
Dhanak
Dashyant
D
Douglas
Stephen A
SA
Giaid
Adel
A
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control; D020869:Gene Expression Profiling; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology*; D014579:Urotensins / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects*; D000096926:Benzenesulfonamides
D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; D014579:Urotensins; C513816:SB-611812; D000096926:Benzenesulfonamides; C473142:Uts2r protein, rat; C029677:urotensin II