Telmisartan Plus Propranolol Improves Liver Fibrosis and Bile Duct Proliferation in the PSC-Like Abcb4−/− Mouse Model
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.
We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the β-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model.
Sixty-five Abcb4−/− 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.
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 α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein.
Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4−/− 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.
KeywordsAbcb4 knockout AT1R-blocker Beta blocker Sclerosing cholangitis Fibrogenesis
α-Smooth muscle actin
- Ang II
Angiotensin converting enzyme
Angiotensin II type 1 receptor
Angiotensin II type 1 receptor blocker
Connective tissue growth factor
Hepatic stellate cell
Primary sclerosing cholangitis
Real-time quantitative reverse transcription polymerase chain reaction
Sympathetic nervous system
Tissue inhibitor of matrix metalloproteinase
- 31.Multi-system analysis of physiology on 7 inbred strains of mice. (Database on the Internet) 2011. Cited 20 Jan 2011. Available from: http://phenome.jax.org.