Abstract
To investigate the effects of miR-98 on TGF-β1-induced cardiac fibrosis in human cardiac fibroblasts (HCFs), and to establish the mechanism underlying these effects, HCFs were transfected with miR-98 inhibitor or mimic, and then treated with or without TGF-β1. The level of miR-98 was determined by qRT-PCR in TGF-β1-induced HCFs. Cell differentiation and collagen accumulation of HCFs were detected by qRT-PCR and Western blot assays, respectively. The mRNA and protein expressions of TGFBR1 were determined by qRT-PCR and Western blotting. In this study, the outcomes showed that TGF-β1 could dramatically decrease the level of miR-98 in a time- and concentration-dependent manner. Upregulation of miR-98 dramatically improved TGF-β1-induced increases in cell differentiation and collagen accumulation of HCFs. Moreover, bioinformatics analysis predicted that the TGFBR1 was a potential target gene of miR-98. Luciferase reporter assay demonstrated that miR-98 could directly target TGFBR1. Inhibition of TGFBR1 had the similar effect as miR-98 overexpression. Downregulation of TGFBR1 in HCFs transfected with miR-98 inhibitor partially reversed the protective effect of miR-98 overexpression on TGF-β1-induced cardiac fibrosis in HCFs. Upregulation of miR-98 ameliorates TGF-β1-induced differentiation and collagen accumulation of HCFs by downregulation of TGFBR1. These results provide further evidence for protective effect of miR-98 overexpression on TGF-β1-induced cardiac fibrosis.
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References
Zhou Y, Deng L, Zhao D, et al. MicroRNA-503 promotes angiotensin II-induced cardiac fibrosis by targeting Apelin-13. J Cell Mol Med. 2016;20(3):495–505.
Zeigler AC, Richardson WJ, Holmes JW, et al. Computational modeling of cardiac fibroblasts and fibrosis. J Mol Cell Cardiol. 2015;93:73–83.
Tao H, Shi KH, Yang JJ, et al. Epigenetic regulation of cardiac fibrosis. Cell Signal. 2013;25(9):1932–8.
Tijsen AJ, van der Made I, van den Hoogenhof MM, et al. The microRNA-15 family inhibits the TGFbeta-pathway in the heart. Cardiovasc Res. 2014;104(1):61–71.
Jiang X, Tsitsiou E, Herrick SE, et al. MicroRNAs and the regulation of fibrosis. FEBS J. 2010;277(9):2015–21.
Dai Y, Khaidakov M, Wang X, et al. MicroRNAs involved in the regulation of postischemic cardiac fibrosis. Hypertension. 2013;61(4):751–6.
van Putten S, Shafieyan Y, Hinz B. Mechanical control of cardiac myofibroblasts. J Mol Cell Cardiol. 2015;93:133–42.
Zhao X, Wang K, Liao Y, et al. MicroRNA-101a inhibits cardiac fibrosis induced by hypoxia via targeting TGFbetaRI on cardiac fibroblasts. Cell Physiol Biochem. 2015;35(1):213–26.
Bei Y, Song Y, Wang F, et al. miR-382 targeting PTEN–Akt axis promotes liver regeneration. Oncotarget. 2016;7(2):1584–97.
Xu T, Zhou Q, Che L, et al. Circulating miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in chronic heart failure patients. Oncotarget. 2016;7(11):12414–25.
Liu X, Xiao J, Zhu H, et al. miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell Metab. 2015;21(4):584–95.
Liang D, Xu X, Deng F, et al. miRNA-940 reduction contributes to human tetralogy of fallot development. J Cell Mol Med. 2014;18(9):1830–9.
Xiao J, Liang D, Zhang H, et al. MicroRNA-204 is required for differentiation of human-derived cardiomyocyte progenitor cells. J Mol Cell Cardiol. 2012;53(6):751–9.
Mai L, Xiao L, Huang Y, et al. Novel microRNAs involved in regulation of cardiac fibrosis. Int J Cardiol. 2015;192:14–5.
Gupta SK, Itagaki R, Zheng X, et al. miR-21 promotes fibrosis in an acute cardiac allograft transplantation model. Cardiovasc Res. 2016;110(2):215–26.
Huang Y, Qi Y, Du JQ, et al. MicroRNA-34a regulates cardiac fibrosis after myocardial infarction by targeting Smad4. Expert Opin Ther Targets. 2014;18(12):1355–65.
Nagpal V, Rai R, Place AT, et al. MiR-125b is critical for fibroblast-to-myofibroblast transition and cardiac fibrosis. Circulation. 2016;133(3):291–301.
Wang X, Wang HX, Li YL, et al. MicroRNA Let-7i negatively regulates cardiac inflammation and fibrosis. Hypertension. 2015;66(4):776–85.
Wang L, Ma L, Fan H, et al. MicroRNA-9 regulates cardiac fibrosis by targeting PDGFR-β in rats. J Physiol Biochem. 2016;72(2):213–23.
Tao H, Chen ZW, Yang JJ, et al. MicroRNA-29a suppresses cardiac fibroblasts proliferation via targeting VEGF-A/MAPK signal pathway. Int J Biol Macromol. 2016;88:414–23.
Sang HQ, Jiang ZM, Zhao QP, et al. MicroRNA-133a improves the cardiac function and fibrosis through inhibiting Akt in heart failure rats. Biomed Pharmacother. 2015;71:185–9.
Zhu W, Yang L, Shan H, et al. MicroRNA expression analysis: clinical advantage of propranolol reveals key microRNAs in myocardial infarction. PLoS One. 2011;6:e14736.
Tao H, Yang JJ, Hu W, et al. Noncoding RNA as regulators of cardiac fibrosis: current insight and the road ahead. Pflugers Arch. 2016;468(6):1103–11.
Tao H, Yang JJ, Shi KH, et al. Wnt signaling pathway in cardiac fibrosis: new insights and directions. Metabolism. 2016;65(2):30–40.
Sun M, Yu H, Zhang Y, et al. MicroRNA-214 mediates isoproterenol-induced proliferation and collagen synthesis in cardiac fibroblasts. Sci Rep. 2015;5:18351.
Pellman J, Lyon RC, Sheikh F. Extracellular matrix remodeling in atrial fibrosis: mechanisms and implications in atrial fibrillation. J Mol Cell Cardiol. 2010;48(3):461–7.
Creemers EE, Pinto YM. Molecular mechanisms that control interstitial fibrosis in the pressure-overloaded heart. Cardiovasc Res. 2011;89(2):265–72.
Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest. 2007;117(3):568–75.
Cucoranu I, Clempus R, Dikalova A, et al. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005;987(9):9800–7.
Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther. 2009;123(2):255–78.
van den Borne SW, Diez J, Blankesteijn WM, et al. Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol. 2010;7(1):30–7.
Rohr S. Myofibroblasts in diseased hearts: new players in cardiac arrhythmias? Heart Rhythm. 2009;6(6):848–56.
Leask A. Potential therapeutic targets for cardiac fibrosis TGFβ, angiotensin, endothelin, CCN2 and PDGF, partners in fibroblast activation. Circ Res. 2010;106(11):1675–80.
Pelouch V, Dixon IM, Golfman L, et al. Role of extracellular matrix proteins in heart function. Mol Cell Biochem. 1993; 129(2): 101–20.
Zhong C, Wang K, Liu Y, et al. miR-198b controls cardiac fibroblast proliferation and migration. J Cell Mol Med. 2016;20(6):11981–7.
Zhou Y, Deng L, Zhao D, et al. MicroRNA-503 promotes angiotensin II-induced cardiac fibrosis by targeting Apelin-13. J Cell Mol Med. 2016;20(3):4985–5505.
Nagpal V, Rai R, Place AT, et al. MiR-125b is critical for fibroblast-to-myofibroblast transition and cardiac fibrosis. Circulation. 2016;133(3):2981–3301.
Zhang Y, Huang XR, Wei LH, et al. miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling. Mol Ther. 2014;22(5):974–85.
Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by transforming growth factor-beta(1). Mol Genetic Metabol. 2000;71(1–2):418–35.
Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-β function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation. 2002;106(1):130–5.
Lim H, Zhu YZ. Role of transforming growth factor-beta in the progression of heart failure. Cell Mol Life Sci. 2006;63(22):2584–96.
Chen J, Mehta JL. Angiotensin II-mediated oxidative stress and procollagen-I expression in cardiac fibroblasts: blockade by pravastatin and pioglitazone. Am J Physiol Heart Circ Physiol. 2006;291(4):H1738–45.
Liu X, Sun SQ, Hassid A, et al. cAMP inhibits transforming growth factor-beta-stimulated collagen synthesis via inhibition of extracellular signal-regulated kinase 1/2 and Smad signaling in cardiac fibroblasts. Mol Pharmacol. 2006;70(6):1992–2003.
Driesen RB, Nagaraju CK, Abi-Char J, et al. Reversible and irreversible differentiation of cardiac fibroblasts. Cardiovasc Res. 2014;101(3):411–22.
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Cheng, R., Dang, R., Zhou, Y. et al. MicroRNA-98 inhibits TGF-β1-induced differentiation and collagen production of cardiac fibroblasts by targeting TGFBR1. Human Cell 30, 192–200 (2017). https://doi.org/10.1007/s13577-017-0163-0
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DOI: https://doi.org/10.1007/s13577-017-0163-0