Telmisartan Plus Propranolol Improves Liver Fibrosis and Bile Duct Proliferation in the PSC-Like Abcb4 super(-/-) Mouse Model

• Published in: Digestive diseases and sciences Vol. 58; no. 5; pp. 1271 - 1281
• Main Authors: Mende, Susanne, Schulte, Sigrid, Strack, Ingo, Hunt, Heike, Odenthal, Margarete, Pryymachuck, Galyna, Quasdorff, Maria, Demir, Muenevver, Nierhoff, Dirk, Dienes, Hans-Peter, Goeser, Tobias, Steffen, Hans-Michael, Tox, Ulrich
• Format: Journal Article
• Language: English
• Published: 01.05.2013
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-012-2499-3

Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin-angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models. Aims: We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the beta -adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model. Methods: Sixty-five Abcb4 super( -/- ) mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting. Results: Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p = 0.008), fibrosis score (TP 3 months and TP 8 months, p = 0.043 and p = 0.008, respectively; TP delayed 8 months, p < 0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p < 0.0005, respectively), and procollagen alpha 1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as alpha -SMA, CK-19, and TIMP-1 protein. Conclusions: Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4 super( -/- ) mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.