Levistilide A reverses rat hepatic fibrosis by suppressing angiotensin II‑induced hepatic stellate cells activation

Li,Shu; Zhao,Wei; Zhao,Zhimin; Cheng,Binbin; Li,Shuang; Liu,Chenghai

doi:10.3892/mmr.2020.11326

Levistilide A reverses rat hepatic fibrosis by suppressing angiotensin II‑induced hepatic stellate cells activation

Authors:
- Shu Li
- Wei Zhao
- Zhimin Zhao
- Binbin Cheng
- Shuang Li
- Chenghai Liu
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Affiliations: Department of Gastroenterology, Baoshan Branch, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201900, P.R. China, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China, Department of Tradition Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: July 10, 2020 https://doi.org/10.3892/mmr.2020.11326
Pages: 2191-2198
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The renin angiotensin system (RAS) serves an important role in the development of hepatic fibrosis. Therefore, the present study investigated the effect of levistilide A (Lev A) on hepatic fibrosis via regulation of RAS. The effects of Lev A on the proliferation and activation of hepatic stellate cells (HSCs) were measured using a 5‑ethynyl‑2'‑deoxyuridine assay, western blot analysis and immunofluorescence. The in vivo anti‑hepatic fibrosis effect of Lev A was examined using a CCL4‑induced rat fibrosis model. Lev A significantly prohibited angiotensin (Ang) II‑induced proliferation of HSCs, and overexpression of smooth muscle α‑actin (α‑SMA) and F‑actin in HSCs. Lev A partly reversed Ang II‑induced angiotensin type 1 receptor (AT1R) upregulation and ERK and c‑Jun phosphorylation. In CCL4‑induced hepatic fibrosis rats, Lev A treatment significantly decreased the expression of collagen, α‑SMA and hydroxyproline in rat liver, and improved liver functions. Lev A treatment also significantly inhibited the CCL4‑induced increase in plasma Ang II, and upregulation of AT1R and phosphorylated ERK in rat liver. In conclusion, Lev A is a potential agent for the treatment of hepatic fibrosis by suppressing Ang II/AT1R/ERK/c‑Jun activation in HSCs.

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1	Khomich O, Ivanov AV and Bartosch B: Metabolic hallmarks of hepatic stellate cells in liver fibrosis. Cells. 9(pii): E242019. View Article : Google Scholar : PubMed/NCBI
2	Huang Y, Deng X and Liang J: Modulation of hepatic stellate cells and reversibility of hepatic fibrosis. Exp Cell Res. 352:420–426. 2017. View Article : Google Scholar : PubMed/NCBI
3	Cai X, Wang J, Zhou Q, Yang B, He Q and Weng Q: Intercellular crosstalk of hepatic stellate cells in liver fibrosis: New insights into therapy. Pharmacol Res. 155:1047202020. View Article : Google Scholar : PubMed/NCBI
4	Sancho-Bru P and Ginès P: Targeting the renin-angiotensin system in liver fibrosis. Hepatol Int. 10:730–732. 2016. View Article : Google Scholar : PubMed/NCBI
5	Li S, Zhao W, Tao Y and Liu C: Fugan Wan alleviates hepatic fibrosis by inhibiting ACE/Ang II/AT-1R signaling pathway and enhancing ACE2/Ang 1-7/Mas signaling pathway in hepatic fibrosis rat models. Am J Transl Res. 12:592–601. 2020.PubMed/NCBI
6	Bataller R, Ginès P, Nicolás JM, Görbig MN, Garcia-Ramallo E, Gasull X, Bosch J, Arroyo V and Rodés J: Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 118:1149–1156. 2000. View Article : Google Scholar : PubMed/NCBI
7	Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ and Brenner DA: NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest. 112:1383–1394. 2003. View Article : Google Scholar : PubMed/NCBI
8	Saber S, Goda R, El-Tanbouly GS and Ezzat D: Lisinopril inhibits nuclear transcription factor kappa B and augments sensitivity to silymarin in experimental liver fibrosis. Int Immunopharmacol. 64:340–349. 2018. View Article : Google Scholar : PubMed/NCBI
9	Czechowska G, Celinski K, Korolczuk A, Wojcicka G, Dudka J, Bojarska A, Madro A and Brzozowski T: The effect of the angiotensin II receptor, type 1 receptor antagonists, losartan and telmisartan, on thioacetamide-induced liver fibrosis in rats. J Physiol Pharmacol. 67:575–586. 2016.PubMed/NCBI
10	Kim MY, Baik SK, Park DH, Jang YO, Suk KT, Yea CJ, Lee IY, Kim JW, Kim HS, Kwon SO, et al: Angiotensin receptor blockers are superior to angiotensin-converting enzyme inhibitors in the suppression of hepatic fibrosis in a bile duct-ligated rat model. J Gastroenterol. 43:889–896. 2008. View Article : Google Scholar : PubMed/NCBI
11	Reza HM, Tabassum N, Sagor MA, Chowdhury MR, Rahman M, Jain P and Alam MA: Angiotensin-converting enzyme inhibitor prevents oxidative stress, inflammation, and fibrosis in carbon tetrachloride-treated rat liver. Toxicol Mech Methods. 26:46–53. 2016. View Article : Google Scholar : PubMed/NCBI
12	Bataller R, Gäbele E, Schoonhoven R, Morris T, Lehnert M, Yang L, Brenner DA and Rippe RA: Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver. Am J Physiol Gastrointest Liver Physiol. 285:G642–G651. 2003. View Article : Google Scholar : PubMed/NCBI
13	Huang Y, Li Y, Lou A, Wang GZ, Hu Y, Zhang Y, Huang W, Wang J, Li Y, Zhu X, et al: Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS. Clin Sci (Lond). 134:853–869. 2020. View Article : Google Scholar : PubMed/NCBI
14	Wei H, Lu H, Li D, Zhan Y, Wang Z and Huang X: The expression of AT1 receptor on hepatic stellate cells in rat fibrosis induced by CCl4. Chin Med J (Engl). 114:583–587. 2001.PubMed/NCBI
15	Wang K, Cao P, Wang H, Tang Z, Wang N, Wang J and Zhang Y: Chronic administration of Angelica sinensis polysaccharide effectively improves fatty liver and glucose homeostasis in high-fat diet-fed mice. Sci Rep. 6:262292016. View Article : Google Scholar : PubMed/NCBI
16	Pu X, Fan W, Yu S, Li Y, Ma X, Liu L, Ren J and Zhang W: Polysaccharides from Angelica and Astragalus exert hepatoprotective effects against carbon-tetrachloride-induced intoxication in mice. Can J Physiol Pharmacol. 93:39–43. 2015. View Article : Google Scholar : PubMed/NCBI
17	Lee TF, Lin YL and Huang YT: Studies on antiproliferative effects of phthalides from Ligusticum chuanxiong in hepatic stellate cells. Planta Med. 73:527–534. 2007. View Article : Google Scholar : PubMed/NCBI
18	Friedman SL, Rockey DC, McGuire RF, Maher JJ, Boyles JK and Yamasaki G: Isolated hepatic lipocytes and Kupffer cells from normal human liver: Morphological and functional characteristics in primary culture. Hepatology. 15:234–243. 1992. View Article : Google Scholar : PubMed/NCBI
19	Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, Groszmann RJ, Dranoff JA, Torok NJ and Mehal WZ: Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition. Hepatology. 49:185–194. 2009. View Article : Google Scholar : PubMed/NCBI
20	Ala-Kokko L, Pihlajaniemi T, Myers JC, Kivirikko KI and Savolainen ER: Gene expression of type I, III and IV collagens in hepatic fibrosis induced by dimethylnitrosamine in the rat. Biochem J. 244:75–79. 1987. View Article : Google Scholar : PubMed/NCBI
21	Li S, Wang Q, Tao Y and Liu C: Swertiamarin attenuates experimental rat hepatic fibrosis by suppressing angiotensin II-angiotensin type 1 receptor-extracellular signal-regulated kinase signaling. J Pharmacol Exp Ther. 359:247–255. 2016. View Article : Google Scholar : PubMed/NCBI
22	Wei HS, Lu HM, Li DG, Zhan YT, Wang ZR, Huang X, Cheng JL and Xu QF: The regulatory role of AT 1 receptor on activated HSCs in hepatic fibrogenesis:Effects of RAS inhibitors on hepatic fibrosis induced by CCl(4). World J Gastroenterol. 6:824–828. 2000. View Article : Google Scholar : PubMed/NCBI
23	Wu Y, Li Z, Wang S, Xiu A and Zhang C: Carvedilol inhibits angiotensin II-induced proliferation and contraction in hepatic stellate cells through the RhoA/Rho-kinase pathway. Biomed Res Int. 2019:79320462019. View Article : Google Scholar : PubMed/NCBI
24	Zhang X, Zhang F, Kong D, Wu X, Lian N, Chen L, Lu Y and Zheng S: Tetramethylpyrazine inhibits angiotensin II-induced activation of hepatic stellate cells associated with interference of platelet-derived growth factor β receptor pathways. FEBS J. 281:2754–2768. 2014. View Article : Google Scholar : PubMed/NCBI
25	Li X, Meng Y, Wu P, Zhang Z and Yang X: Angiotensin II and aldosterone stimulating NF-kappaB and AP-1 activation in hepatic fibrosis of rat. Regul Pept. 138:15–25. 2007. View Article : Google Scholar : PubMed/NCBI
26	Yang L, Bataller R, Dulyx J, Coffman TM, Ginès P, Rippe RA and Brenner DA: Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice. J Hepatol. 43:317–323. 2005. View Article : Google Scholar : PubMed/NCBI
27	Wang XN, Hu YY, Liu CH, Liu P and Zhu DY: Effects of salvianolic acid B on expressions of TGF-beta1 and its receptors in liver of rats with dimethylnitrosamine-induced hepatic fibrosis. Zhong Xi Yi Jie He Xue Bao. 3:286–289. 2005.(In Chinese). View Article : Google Scholar : PubMed/NCBI
28	Ruiz-Ortega M, Lorenzo O, Rupérez M, Suzuki Y and Egido J: Angiotensin II activates nuclear transcription factor-kappaB in aorta of normal rats and in vascular smooth muscle cells of AT1 knockout mice. Nephrol Dial Transplant. 16 (Suppl 1):S27–S33. 2001. View Article : Google Scholar
29	Vogt PK: Jun, the oncoprotein. Oncogene. 20:2365–2377. 2001. View Article : Google Scholar : PubMed/NCBI
30	Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, et al: A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res. 87:E1–E9. 2000. View Article : Google Scholar : PubMed/NCBI
31	Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G and Turner AJ: A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril- insensitive carboxypeptidase. J Biol Chem. 275:33238–33243. 2000. View Article : Google Scholar : PubMed/NCBI
32	Santos RA, Ferreira AJ, Verano-Braga T and Bader M: Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: New players of the renin-angiotensin system. J Endocrinol. 216:R1–R17. 2013. View Article : Google Scholar : PubMed/NCBI
33	Lubel JS, Herath CB, Tchongue J, Grace J, Jia Z, Spencer K, Casley D, Crowley P, Sievert W, Burrell LM and Angus PW: Angiotensin-(1–7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat. Clin Sci (Lond). 117:375–386. 2009. View Article : Google Scholar : PubMed/NCBI
34	Dasuri K, Zhang L and Keller JN: Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic Biol Med. 62:170–185. 2013. View Article : Google Scholar : PubMed/NCBI
35	Herath CB, Warner FJ, Lubel JS, Dean RG, Jia Z, Lew RA, Smith AI, Burrell LM and Angus PW: Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1–7) levels in experimental biliary fibrosis. J Hepatol. 47:387–395. 2007. View Article : Google Scholar : PubMed/NCBI
36	Pereira RM, Dos Santos RA, Teixeira MM, Leite VH, Costa LP, da Costa Dias FL, Barcelos LS, Collares GB and Simões e Silva AC: The renin-angiotensin system in a rat model of hepatic fibrosis: Evidence for a protective role of Angiotensin-(1-7). J Hepatol. 46:674–681. 2007. View Article : Google Scholar : PubMed/NCBI
37	Wang X, Ye Y, Gong H, Wu J, Yuan J, Wang S, Yin P, Ding Z, Kang L, Jiang Q, et al: The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1–7)-Mas axes in pressure overload-induced cardiac remodeling in male mice. J Mol Cell Cardiol. 97:180–190. 2016. View Article : Google Scholar : PubMed/NCBI