Urantide decreases hepatic steatosis in rats with experimental atherosclerosis via the MAPK/Erk/JNK pathway

Cui,Haipeng; Lin,Yingxue; Xie,Lide; Zhao,Juan

doi:10.3892/mmr.2021.11923

Urantide decreases hepatic steatosis in rats with experimental atherosclerosis via the MAPK/Erk/JNK pathway

Authors:
- Haipeng Cui
- Yingxue Lin
- Lide Xie
- Juan Zhao
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Affiliations: Department of Pathophysiology, Chengde Medical University, Chengde, Hebei 067000, P.R. China, Department of Medicine, Affiliated Hospital of Chengde Medical University, Chengde, Hebei 067000, P.R. China
Published online on: February 18, 2021 https://doi.org/10.3892/mmr.2021.11923
Article Number: 284
Copyright: © Cui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatic steatosis, an indicator of atherosclerosis (AS), is always accompanied by inflammatory responses and disturbances in lipid metabolism. The present study investigated the protective effect of urantide, a urotensin II (UII) receptor antagonist, on the liver of rats with AS with hepatic steatosis by regulating the MAPK pathway. AS was induced in rats via an intraperitoneal injection of vitamin D3 and the administration of a high‑fat diet. Urantide treatment was then administered to the rats. Pathology, liver index, lipid levels and liver function were measured to determine liver injury. The expression levels of UII and G protein‑coupled receptor 14 (GPR14) were determined using immunohistochemistry, reverse transcription‑quantitative PCR and western blotting. The expression levels of MAPK‑related proteins in hepatocytes from each group were quantified using western blotting and immunofluorescence staining. Rats with AS had typical pathological changes associated with AS and hepatic steatosis, which were significantly improved by urantide treatment. Blood lipid levels, body weight, liver index and liver function were recovered in rats with AS after urantide treatment. Urantide downregulated the expression levels of UII and GPR14 in the livers of rats with AS; concurrently, the phosphorylation of Erk1/2 and JNK was significantly decreased. Moreover, no significant changes were observed in the phosphorylation of p38 MAPK in AS rat livers. In conclusion, urantide inhibits the activation of Erk1/2 and JNK by blocking the binding of UII and GPR14, thereby alleviating hepatic steatosis in rats with AS, ultimately restoring lipid metabolism in the liver and alleviating AS lesions.

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1	Gaudio E, Nobili V, Franchitto A, Onori P and Carpino G: Nonalcoholic fatty liver disease and atherosclerosis. Intern Emerg Med. 7 (Suppl 3):S297–S305. 2012. View Article : Google Scholar : PubMed/NCBI
2	Guth S, Windler E, Leise U and Bamberger CM: Ultrasound Diagnosis of Hepatic Steatosis as a Surrogate for Atherosclerosis. Ultrasound Int Open. 2:E27–E31. 2016. View Article : Google Scholar : PubMed/NCBI
3	Kapuria D, Takyar VK, Etzion O, Surana P, O'Keefe JH and Koh C: Association of Hepatic Steatosis With Subclinical Atherosclerosis: Systematic Review and Meta-Analysis. Hepatol Commun. 2:873–883. 2018. View Article : Google Scholar : PubMed/NCBI
4	Ross B, McKendy K and Giaid A: Role of urotensin II in health and disease. Am J Physiol Regul Integr Comp Physiol. 298:R1156–R1172. 2010. View Article : Google Scholar : PubMed/NCBI
5	Brancaccio D, Limatola A, Campiglia P, Gomez-Monterrey I, Novellino E, Grieco P and Carotenuto A: Urantide conformation and interaction with the urotensin-II receptor. Arch Pharm (Weinheim). 347:185–192. 2014. View Article : Google Scholar : PubMed/NCBI
6	Svistunov AA, Tarasov VV, Shakhmardanova SA, Sologova SS, Bagaturiya ET, Chubarev VN, Galenko-Yaroshevsky PA, Avila-Rodriguez MF, Barreto GE and Aliev G: Urotensin II: Molecular Mechanisms of Biological Activity. Curr Protein Pept Sci. 19:924–934. 2018. View Article : Google Scholar : PubMed/NCBI
7	Bigeard J and Hirt H: Nuclear Signaling of Plant MAPKs. Front Plant Sci. 9:4692018. View Article : Google Scholar : PubMed/NCBI
8	Keshet Y and Seger R: The MAP kinase signaling cascades: A system of hundreds of components regulates a diverse array of physiological functions. Methods Mol Biol. 661:3–38. 2010. View Article : Google Scholar : PubMed/NCBI
9	Ziltener P, Mueller C, Haenig B, Scherz MW and Nayler O: Urotensin II mediates ERK1/2 phosphorylation and proliferation in GPR14-transfected cell lines. J Recept Signal Transduct Res. 22:155–168. 2002. View Article : Google Scholar : PubMed/NCBI
10	Zhao J, Yu QX, Kong W, Gao HC, Sun B, Xie YQ and Ren LQ: The urotensin II receptor antagonist, urantide, protects against atherosclerosis in rats. Exp Ther Med. 5:1765–1769. 2013. View Article : Google Scholar : PubMed/NCBI
11	Zhao J, Xie LD, Song CJ, Mao XX, Yu HR, Yu QX, Ren LQ, Shi Y, Xie YQ, Li Y, et al: Urantide improves atherosclerosis by controlling C-reactive protein, monocyte chemotactic protein-1 and transforming growth factor-β expression in rats. Exp Ther Med. 7:1647–1652. 2014. View Article : Google Scholar : PubMed/NCBI
12	Gou SH, Liu BJ, Han XF, Wang L, Zhong C, Liang S, Liu H, Qiang Y, Zhang Y and Ni JM: Anti-atherosclerotic effect of Fermentum Rubrum and Gynostemma pentaphyllum mixture in high-fat emulsion- and vitamin D3-induced atherosclerotic rats. J Chin Med Assoc. 81:398–408. 2018. View Article : Google Scholar : PubMed/NCBI
13	Huang ZY and Yang PY, Almofti MR, Yu YL, Rui YC and Yang PY: Comparative analysis of the proteome of left ventricular heart of arteriosclerosis in rat. Life Sci. 75:3103–3115. 2004. View Article : Google Scholar : PubMed/NCBI
14	Li X, Li X, Luo R, Wang W, Wang T and Tang H: Detection of KIT genotype in pigs by TaqMan MGB real-time quantitative polymerase chain reaction. DNA Cell Biol. 37:457–464. 2018. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Lu YW, Zhu YC, Zhang L, Li P, Yang J and Wen XD: Ilexgenin A enhances the effects of simvastatin on non-alcoholic fatty liver disease without changes in simvastatin pharmacokinetics. Chin J Nat Med. 16:436–445. 2018.PubMed/NCBI
17	Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, Cigolini M, Falezza G and Arcaro G: Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care. 29:1325–1330. 2006. View Article : Google Scholar : PubMed/NCBI
18	Di Minno MN, Di Minno A, Ambrosino P, Songia P, Tremoli E and Poggio P: Aortic valve sclerosis as a marker of atherosclerosis: Novel insights from hepatic steatosis. Int J Cardiol. 217:1–6. 2016. View Article : Google Scholar : PubMed/NCBI
19	Lee SB, Park GM, Lee JY, Lee BU, Park JH, Kim BG, Jung SW, Jeong ID, Bang SJ, Shin JW, et al: Association between non-alcoholic fatty liver disease and subclinical coronary atherosclerosis: An observational cohort study. J Hepatol. 68:1018–1024. 2018. View Article : Google Scholar : PubMed/NCBI
20	Pearson D, Shively JE, Clark BR, Geschwind II, Barkley M, Nishioka RS and Bern HA: Urotensin II: A somatostatin-like peptide in the caudal neurosecretory system of fishes. Proc Natl Acad Sci USA. 77:5021–5024. 1980. View Article : Google Scholar : PubMed/NCBI
21	Gabunia K, Jain S, England RN and Autieri MV: Anti-inflammatory cytokine interleukin-19 inhibits smooth muscle cell migration and activation of cytoskeletal regulators of VSMC motility. Am J Physiol Cell Physiol. 300:C896–C906. 2011. View Article : Google Scholar : PubMed/NCBI
22	Segain JP, Rolli-Derkinderen M, Gervois N, Raingeard de la Blétière D, Loirand G and Pacaud P: Urotensin II is a new chemotactic factor for UT receptor-expressing monocytes. J Immunol. 179:901–909. 2007. View Article : Google Scholar : PubMed/NCBI
23	Watanabe T, Suguro T, Kanome T, Sakamoto Y, Kodate S, Hagiwara T, Hongo S, Hirano T, Adachi M and Miyazaki A: Human urotensin II accelerates foam cell formation in human monocyte-derived macrophages. Hypertension. 46:738–744. 2005. View Article : Google Scholar : PubMed/NCBI
24	Sun H, Zhang L and Shen D: Urantide protects CCl4-induced liver injury via inhibiting GPR14 signal in mice. Biotechnol Biotechnol Equip. 31:156–161. 2017. View Article : Google Scholar
25	Liang DY, Liu LM, Ye CG, Zhao L, Yu FP, Gao DY and Wang YY, Yang ZW and Wang YY: Inhibition of UII/UTR system relieves acute inflammation of liver through preventing activation of NF-κB pathway in ALF mice. PLoS One. 8:e648952013. View Article : Google Scholar : PubMed/NCBI
26	Liu LM, Zhao L, Liang DY, Yu FP, Ye CG, Tu WJ and Zhu T: Effects of urotensin-II on cytokines in early acute liver failure in mice. World J Gastroenterol. 21:3239–3244. 2015. View Article : Google Scholar : PubMed/NCBI
27	Watanabe T, Kanome T, Miyazaki A and Katagiri T: Human urotensin II as a link between hypertension and coronary artery disease. Hypertens Res. 29:375–387. 2006. View Article : Google Scholar : PubMed/NCBI
28	Cseh B, Doma E and Baccarini M: ‘RAF’ neighborhood: Protein-protein interaction in the Raf/Mek/Erk pathway. FEBS Lett. 588:2398–2406. 2014. View Article : Google Scholar : PubMed/NCBI
29	Hwang HJ, Jung TW, Hong HC, Seo JA, Kim SG, Kim NH, Choi KM, Choi DS, Baik SH and Yoo HJ: LECT2 induces atherosclerotic inflammatory reaction via CD209 receptor-mediated JNK phosphorylation in human endothelial cells. Metabolism. 64:1175–1182. 2015. View Article : Google Scholar : PubMed/NCBI
30	Reustle A and Torzewski M: Role of p38 MAPK in atherosclerosis and aortic valve sclerosis. Int J Mol Sci. 19:37612018. View Article : Google Scholar
31	Kardakaris R, Gareus R, Xanthoulea S and Pasparakis M: Endothelial and macrophage-specific deficiency of P38α MAPK does not affect the pathogenesis of atherosclerosis in ApoE-/- mice. PLoS One. 6:e210552011. View Article : Google Scholar : PubMed/NCBI
32	Leprince J, Chatenet D, Dubessy C, Fournier A, Pfeiffer B, Scalbert E, Renard P, Pacaud P, Oulyadi H, Ségalas-Milazzo I, et al: Structure-activity relationships of urotensin II and URP. Peptides. 29:658–673. 2008. View Article : Google Scholar : PubMed/NCBI
33	Guidolin D, Albertin G and Ribatti D: Urotensin-II as an angiogenic factor. Peptides. 31:1219–1224. 2010. View Article : Google Scholar : PubMed/NCBI
34	Wang T, Sun X, Cui H, Liu K and Zhao J: The peptide compound urantide regulates collagen metabolism in atherosclerotic rat hearts and inhibits the JAK2/STAT3 pathway. Mol Med Rep. 21:1097–1106. 2020.PubMed/NCBI
35	Wang T, Xie YQ, Miao GX, Cui HP, Liu K, Li Y, Li Y and Zhao J: Urotensin receptor antagonist urantide improves atherosclerosis-related kidney injury by inhibiting JAK2/STAT3 signaling pathway in rats. Life Sci. 247:1174212020. View Article : Google Scholar : PubMed/NCBI