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

Lei Zheng; Zhifeng Zhao; Jiayun Lin; Hongjie Li; Guangbo Wu; Xiaoliang Qi; Xiaolou Lou; Yongyang Bao; Haizhong Huo; Meng Luo

doi:10.1016/j.ejphar.2021.174713

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

Eur J Pharmacol. 2022 Jan 15:915:174713. doi: 10.1016/j.ejphar.2021.174713. Epub 2021 Dec 21.

Authors

Lei Zheng¹, Zhifeng Zhao¹, Jiayun Lin¹, Hongjie Li¹, Guangbo Wu¹, Xiaoliang Qi¹, Xiaolou Lou¹, Yongyang Bao², Haizhong Huo³, Meng Luo⁴

Affiliations

¹ Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: yybaodr28@sina.com.
³ Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: hzhhuodr7@sina.com.
⁴ Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: luosh9hospital@sina.com.

PMID: 34942161
DOI: 10.1016/j.ejphar.2021.174713

Abstract

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-α(TNF-α) were significantly decreased after TEL treatment. Moreover, in the liver fibrotic area, the expressions of α-smooth muscle actin(α-SMA), collagen1a1(Col1a1), desmin, transforming growth factor-β(TGF-β), and hydroxyproline, and serum hyaluronic 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-β(PDGF-β), 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 Krüppel-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.

Keywords: Liver fibrosis; Portal hypertension; Telmisartan.

MeSH terms

Telmisartan*

Substances

Telmisartan