Telmisartan relieves liver fibrosis and portal hypertension by improving vascular remodeling and sinusoidal dysfunction

Backgrounds: Telmisartan(TEL) has demonstrated anti-fibrotic and blood pressure lowering effect in various diseases. In this study, we aimed to explore the beneficial effects of TEL on portal hypertension(PHT). Methods: Two models of cirrhosis-induced PHT were involved including carbon tetrachloride injection(CCl4) and bile duct ligation(BDL). Rats were orally gavaged with TEL for 4 weeks. After that, the portal pressure(PP) was determined, and liver and mesenteric tissue specimens were collected to evaluate inflammatory response, liver fibrosis, vascular remodeling, angiogenesis, etc. Results: In CCl4 PHT models, TEL decreased PP significantly from 12.79 +/- 2.92 to 6.91 +/- 1.19 mmHg(p < 0.05). In inflammatory response, hepatic expressions of interleukin(IL)-6, lipopolysaccharide(LPS), and tumor necrosis factor-alpha(TNF-alpha) were significantly decreased after TEL treatment. Moreover, in the liver fibrotic area, the expressions of alpha-smooth muscle actin(alpha-SMA), collagenl a1(Col1a1), desmin, transforming growth factor-beta(TGF-beta), and hydroxyproline, and serum hyalumnic acid were significantly decreased after TEL treatment. Additionally, the expressions of von Willebrand factor(vWF), vascular endothelial growth factor(VEGF) and platelet-derived growth factor-beta(PDGF-beta), matrix metallopeptidase(MMP)-2, and MMP-9 were ameliorated in liver sinusoid, while the expressions of MMP-2 and vWF were reduced in mesenteric arteries after TEL treatment. Meanwhile, TEL treatment up-regulated the hepatic expressions of an anti-fibrotic factor Kriippel-like factor-4(KLF-4) and its downstream endothelial nitric oxide synthase(eNOS) in rats with PHT. The performance of TEL in BDL model was similar but slightly weaker. Conclusions: TEL ameliorated the cirrhosis-induced PHT by reducing liver fibrosis, inflammation responses, angiogenesis, and vascular remodeling. Collectively, KLF-4 and eNOS were the possible molecular targets for the management of cirrhosis-associated PHT.