Basic Investigation| Volume 365, ISSUE 4, P375-385, April 2023

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MicroRNA-19 upregulation attenuates cardiac fibrosis via targeting connective tissue growth factor

Published:December 16, 2022DOI:



      Previous studies have shown the role of microRNA (miR)-19 in aging-related heart failure. The present study aimed to verify the effects of miR-19 on cardiac fibrosis and its target.


      Cardiac fibrosis was induced by myocardial infarction (MI)-induced heart failure and angiotensin (Ang) II-treated rats in vivo, and was induced in Ang II-treated cardiac fibroblasts (CFs) in vitro.


      The expression of miR-19 was reduced in the heart tissue of MI and Ang II-treated rats, and Ang II-treated CFs. The impaired cardiac function in rats was repaired after miR-19 administration. The levels of collagen I, collagen III and transforming growth factor-beta (TGF-β) increased in the heart tissue of MI and Ang II-treated rats, and Ang II-treated CFs. These increases were reversed by miR-19 agomiR. Moreover, the bioinformatic analysis and luciferase reporter assays demonstrated that connective tissue growth factor (CTGF) was a direct target of miR-19. MiR-19 treatment inhibited CTGF expression in CFs, while CTGF overexpression inhibited miR-19 agomiR to attenuate the Ang II-induced increases of collagen I and collagen III in CFs. The increases of p-ERK, p-JNK and p-p38 in the CFs induced by Ang II were repressed by miR-19 agomiR.


      Upregulating miR-19 can improve cardiac function and attenuate cardiac fibrosis by inhibiting the CTGF and MAPK pathways.

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        • Borlaug B.A.
        Evaluation and management of heart failure with preserved ejection fraction.
        Nat Rev Cardiol. 2020; 17: 559-573
        • Stanley W.C.
        • Recchia F.A.
        • Lopaschuk G.D.
        Myocardial substrate metabolism in the normal and failing heart.
        Physiol Rev. 2005; 85: 1093-1129
        • Jessup M.
        • Brozena S.
        Heart failure.
        N Engl J Med. 2003; 348: 2007-2018
        • Sygitowicz G.
        • Maciejak-Jastrzebska A.
        • Sitkiewicz D.
        MicroRNAs in the development of left ventricular remodeling and postmyocardial infarction heart failure.
        Pol Arch Intern Med. 2020; 130: 59-65
        • Luczak E.D.
        • Wu Y.
        • Granger J.M.
        • et al.
        Mitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy.
        Nat Commun. 2020; 11: 4416
        • Tarone G.
        • Balligand J.L.
        • Bauersachs J.
        • et al.
        Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology.
        Eur J Heart Fail. 2014; 16: 494-508
        • Cheng X.
        • Wang L.
        • Wen X.
        • et al.
        TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-beta/Smads and ERK1/2 signaling pathways.
        EBioMedicine. 2021; 67103370
        • Kong P.
        • Christia P.
        • Frangogiannis N.G.
        The pathogenesis of cardiac fibrosis.
        Cell Mol Life Sci. 2014; 71: 549-574
        • Heineke J.
        • Molkentin J.D.
        Regulation of cardiac hypertrophy by intracellular signalling pathways.
        Nat Rev Mol Cell Biol. 2006; 7: 589-600
        • Berk B.C.
        • Fujiwara K.
        • Lehoux S.
        ECM remodeling in hypertensive heart disease.
        J Clin Invest. 2007; 117: 568-575
        • Tallquist M.D.
        • Molkentin J.D.
        Redefining the identity of cardiac fibroblasts.
        Nat Rev Cardiol. 2017; 14: 484-491
        • Bartel D.P.
        MicroRNAs: genomics, biogenesis, mechanism, and function.
        Cell. 2004; 116: 281-297
        • Javadian M.
        • Gharibi T.
        • Shekari N.
        • et al.
        The role of microRNAs regulating the expression of matrix metalloproteinases (MMPs) in breast cancer development, progression, and metastasis.
        J Cell Physiol. 2018; 234: 5399-5412
        • van Rooij E.
        The art of microRNA research.
        Circ Res. 2011; 108: 219-234
        • Mohr A.M.
        • Mott J.L.
        Overview of microRNA biology.
        Semin Liver Dis. 2015; 35: 3-11
        • Melman Y.F.
        • Shah R.
        • Das S.
        MicroRNAs in heart failure: is the picture becoming less miRky?.
        Circ Heart Fail. 2014; 7: 203-214
        • Tijsen A.J.
        • Pinto Y.M.
        • Creemers E.E.
        Non-cardiomyocyte microRNAs in heart failure.
        Cardiovasc Res. 2012; 93: 573-582
        • van Almen G.C.
        • Verhesen W.
        • van Leeuwen R.E.
        • et al.
        MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure.
        Aging Cell. 2011; 10: 769-779
        • Ramazani Y.
        • Knops N.
        • Elmonem M.A.
        • et al.
        Connective tissue growth factor (CTGF) from basics to clinics.
        Matrix Biol. 2018; 68-69: 44-66
        • Vainio L.E.
        • Szabo Z.
        • Lin R.
        • et al.
        Connective tissue growth factor inhibition enhances cardiac repair and limits fibrosis after myocardial infarction.
        JACC Basic Transl Sci. 2019; 4: 83-94
        • Gan X.B.
        • Duan Y.C.
        • Xiong X.Q.
        • et al.
        Inhibition of cardiac sympathetic afferent reflex and sympathetic activity by baroreceptor and vagal afferent inputs in chronic heart failure.
        PLoS One. 2011; 6: e25784
        • Yang Z.
        • Zhang X.
        • Guo N.
        • Li B.
        • Zhao S.
        Substance P inhibits the collagen synthesis of rat myocardial fibroblasts induced by Ang II.
        Med Sci Monit. 2016; 22: 4937-4946
        • Yang X.
        • Wang Y.
        • Yan S.
        • et al.
        Effect of testosterone on the proliferation and collagen synthesis of cardiac fibroblasts induced by angiotensin II in neonatal rat.
        Bioengineered. 2017; 8: 14-20
        • Antoniak S.
        • Sparkenbaugh E.
        • Pawlinski R.
        Tissue factor, protease activated receptors and pathologic heart remodelling.
        Thromb Haemost. 2014; 112: 893-900
        • Lewis A.
        • Mehta S.
        • Hanna L.N.
        • et al.
        Low serum levels of MicroRNA-19 are associated with a stricturing crohn's disease phenotype.
        Inflamm Bowel Dis. 2015; 21: 1926-1934
        • Yu Y.
        • Sun J.
        • Liu J.
        • Wang P.
        • Wang C.
        Ginsenoside Re preserves cardiac function and ameliorates left ventricular remodeling in a rat model of myocardial infarction.
        J Cardiovasc Pharmacol. 2020; 75: 91-97
        • Wu Y.
        • Hu Z.
        • Wang D.
        • Lv K.
        • Hu N.
        Resiniferatoxin reduces ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord in rats.
        Eur J Pharmacol. 2020; 867172836
        • Fei L.
        • Zhang J.
        • Niu H.
        • Yuan C.
        • Ma X.
        Effects of rosuvastatin and MiR-126 on myocardial injury induced by acute myocardial infarction in rats: role of vascular endothelial growth factor a (VEGF-A).
        Med Sci Monit. 2016; 22: 2324-2334
        • Zhang D.Y.
        • Wang B.J.
        • Ma M.
        • Yu K.
        • Zhang Q.
        • Zhang X.W.
        Correction to: MicroRNA-325-3p protects the heart after myocardial infarction by inhibiting RIPK3 and programmed necrosis in mice.
        BMC Mol Biol. 2019; 20: 18
        • Moore-Morris T.
        • Guimaraes-Camboa N.
        • Banerjee I.
        • et al.
        Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis.
        J Clin Invest. 2014; 124: 2921-2934
        • Medzikovic L.
        • Aryan L.
        • Eghbali M.
        Connecting sex differences, estrogen signaling, and microRNAs in cardiac fibrosis.
        J Mol Med (Berl). 2019; 97: 1385-1398
        • Kura B.
        • Szeiffova Bacova B.
        • Kalocayova B.
        • Sykora M.
        • Slezak J.
        Oxidative stress-responsive MicroRNAs in heart injury.
        Int J Mol Sci. 2020; 21: 358
        • Dorn L.E.
        • Petrosino J.M.
        • Wright P.
        • Accornero F.
        CTGF/CCN2 is an autocrine regulator of cardiac fibrosis.
        J Mol Cell Cardiol. 2018; 121: 205-211
        • Bretherton R.
        • Bugg D.
        • Olszewski E.
        • Davis J.
        Regulators of cardiac fibroblast cell state.
        Matrix Biol. 2020; 91-92: 117-135
        • Zhao T.
        • Kee H.J.
        • Bai L.
        • Kim M.K.
        • Kee S.J.
        • Jeong M.H.
        Selective HDAC8 inhibition attenuates isoproterenol-induced cardiac hypertrophy and fibrosis via p38 MAPK pathway.
        Front Pharmacol. 2021; 12677757
        • Liu Z.
        • Gao Z.
        • Zeng L.
        • Liang Z.
        • Zheng D.
        • Wu X.
        Nobiletin ameliorates cardiac impairment and alleviates cardiac remodeling after acute myocardial infarction in rats via JNK regulation.
        Pharmacol Res Perspect. 2021; 9: e00728