Urotensin-II receptor blockade with SB-611812 attenuates cardiac remodeling in experimental ischemic heart disease Nicolas Bousette a , Julia Pottinger a , Wisam Ramli a , Eliot H. Ohlstein b , Dashyant Dhanak c , Stephen A. Douglas b , Adel Giaid a, * a Division of Cardiology, Montreal General Hospital, McGill University Health Center, Suite L3-109, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada b The Cardiovascular and Urogenital-CEDD, GlaxoSmithKline, King of Prussia, PA 19406, USA c Microbial, Musculoskeletal and Proliferative Diseases CEDD, GlaxoSmithKline, Collegeville, PA 19426, USA 1. Introduction Urotensin-II is a small peptide with pleiotropic effects remi- niscent of endothelin-1. UII binds a G-protein coupled receptor which activates a variety of intracellular signaling molecules [16,18]. UII and its receptor, UT, are widely expressed through- out the body particularly in the cardiovascular system [1,5]. We have previously demonstrated increased expression of UII and UT in the heart of patients with end-stage congestive heart failure due to either dilated or ischemic cardiomyopathy [4]. In the same study we showed that UII levels were significantly correlated with left ventricular end-diastolic dimension and peptides 27 (2006) 2919–2926 article info Article history: Received 26 May 2006 Received in revised form 28 June 2006 Accepted 29 June 2006 Published on line 17 August 2006 Keywords: Rat Myocardial infarction Fibrosis Collagen Urotensin-II abstract 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 mM 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. # 2006 Elsevier Inc. All rights reserved. * Corresponding author. Tel.: +1 514 934 1934x43841; fax: +1 514 934 8344. E-mail address: adel.giaid@mcgill.ca (A. Giaid). available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/peptides 0196-9781/$ – see front matter # 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2006.06.011