Open Access

miR‑216a exacerbates TGF‑β‑induced myofibroblast transdifferentiation via PTEN/AKT signaling

  • Authors:
    • Chuan Qu
    • Xin Liu
    • Tianxin Ye
    • Linglin Wang
    • Steven Liu
    • Xingyu Zhou
    • Gang Wu
    • Jian Lin
    • Shaobo Shi
    • Bo Yang
  • View Affiliations

  • Published online on: April 30, 2019     https://doi.org/10.3892/mmr.2019.10200
  • Pages: 5345-5352
  • Copyright: © Qu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Myofibroblast transdifferentiation is an important feature of cardiac fibrosis. Previous studies have indicated that microRNA‑216a (miR‑216a) is upregulated in response to transforming growth factor‑β (TGF‑β) in kidney cells and can activate Smad3; however, its role in myofibroblast transdifferentiation remains unclear. The present study aimed to investigate the role of miR‑216a in TGF‑β‑induced myofibroblast transdifferentiation, and to determine the underlying mechanisms. Adult mouse cardiac fibroblasts were treated with TGF‑β to induce myofibroblast transdifferentiation. An antagomir and agomir of miR‑216a were used to inhibit or overexpress miR‑216a in cardiac fibroblasts, respectively. Myofibroblast transdifferentiation was evaluated based on the levels of fibrotic markers and α‑smooth muscle actin expression. The miR‑216a antagomir attenuated, whereas the miR‑216a agomir promoted TGF‑β‑induced myofibroblast transdifferentiation. Mechanistically, miR‑216a accelerated myofibroblast transdifferentiation via the AKT/glycogen synthase kinase 3β signaling pathway, independent of the canonical Smad3 pathway. In addition, it was observed that miR‑216a activated AKT via the downregulation of PTEN. In conclusion, miR‑216a was involved in the regulation of TGF‑β‑induced myofibroblast transdifferentiation, suggesting that targeting miR‑216a may aid in developing effective interventions for the treatment of cardiac fibrosis.

References

1 

Kong P, Christia P and Frangogiannis NG: The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 71:549–574. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Nguyen TP, Qu Z and Weiss JN: Cardiac fibrosis and arrhythmogenesis: The road to repair is paved with perils. J Mol Cell Cardiol. 70:83–91. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Coronel R, Wilders R, Verkerk AO, Wiegerinck RF, Benoist D and Bernus O: Electrophysiological changes in heart failure and their implications for arrhythmogenesis. Biochim Biophys Acta. 1832:2432–2441. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, et al: Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J Clin Invest. 120:3520–3529. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Meng XM, Nikolic-Paterson DJ and Lan HY: TGF-β: The master regulator of fibrosis. Nat Rev Nephrol. 12:325–338. 2016. View Article : Google Scholar : PubMed/NCBI

6 

Khalil H, Kanisicak O, Prasad V, Correll RN, Fu X, Schips T, Vagnozzi RJ, Liu R, Huynh T, Lee SJ, et al: Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest. 127:3770–3783. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Molkentin JD, Bugg D, Ghearing N, Dorn LE, Kim P, Sargent MA, Gunaje J, Otsu K and Davis J: Fibroblast-specific genetic manipulation of p38 mitogen-activated protein kinase in vivo reveals its central regulatory role in fibrosis. Circulation. 136:549–561. 2017. View Article : Google Scholar : PubMed/NCBI

8 

Ma ZG, Yuan YP, Zhang X, Xu SC, Wang SS and Tang QZ: Piperine attenuates pathological cardiac fibrosis via PPAR-γ/AKT pathways. EBioMedicine. 18:179–187. 2017. View Article : Google Scholar : PubMed/NCBI

9 

Vivar R, Humeres C, Ayala P, Olmedo I, Catalán M, Garcia L, Lavandero S and Diaz-Araya G: TGF-β1 prevents simulated ischemia/reperfusion-induced cardiac fibroblast apoptosis by activation of both canonical and non-canonical signaling pathways. Biochim Biophys Acta. 1832:754–762. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Zaidi SH, Huang Q, Momen A, Riazi A and Husain M: Growth differentiation factor 5 regulates cardiac repair after myocardial infarction. J Am Coll Cardiol. 55:135–143. 2010. View Article : Google Scholar : PubMed/NCBI

11 

Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI

12 

Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI

13 

Jiang X, Tsitsiou E, Herrick SE and Lindsay MA: MicroRNAs and the regulation of fibrosis. FEBS J. 277:2015–2021. 2010. View Article : Google Scholar : PubMed/NCBI

14 

Dai Y, Khaidakov M, Wang X, Ding Z, Su W, Price E, Palade P, Chen M and Mehta JL: MicroRNAs involved in the regulation of postischemic cardiac fibrosis. Hypertension. 61:751–756. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Matkovich SJ, Wang W, Tu Y, Eschenbacher WH, Dorn LE, Condorelli G, Diwan A, Nerbonne JM and Dorn GN II: MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts. Circ Res. 106:166–175. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Pan Z, Sun X, Shan H, Wang N, Wang J, Ren J, Feng S, Xie L, Lu C, Yuan Y, et al: MicroRNA-101 inhibited postinfarct cardiac fibrosis and improved left ventricular compliance via the FBJ osteosarcoma oncogene/transforming growth factor-β1 pathway. Circulation. 126:840–850. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Nagpal V, Rai R, Place AT, Murphy SB, Verma SK, Ghosh AK and Vaughan DE: MiR-125b is critical for fibroblast-to-myofibroblast transition and cardiac fibrosis. Circulation. 133:291–301. 2016. View Article : Google Scholar : PubMed/NCBI

18 

Kato M, Putta S, Wang M, Yuan H, Lanting L, Nair I, Gunn A, Nakagawa Y, Shimano H, Todorov I, et al: TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN. Nat Cell Biol. 11:881–889. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Hou BH, Jian ZX, Cui P, Li SJ, Tian RQ and Ou JR: miR-216a may inhibit pancreatic tumor growth by targeting JAK2. FEBS Lett. 589:2224–2232. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Xia H, Ooi LL and Hui KM: MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 58:629–641. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Yang S, Mi X, Chen Y, Feng C, Hou Z, Hui R and Zhang W: MicroRNA-216a induces endothelial senescence and inflammation via Smad3/IκBα pathway. J Cell Mol Med. 22:2739–2749. 2018. View Article : Google Scholar : PubMed/NCBI

22 

Yang S, Li J, Chen Y, Zhang S, Feng C, Hou Z, Cai J, Wang Y, Hui R, Lv B and Zhang W: MicroRNA-216a promotes M1 macrophages polarization and atherosclerosis progression by activating telomerase via the Smad3/NF-κB pathway. Biochim Biophys Acta Mol Basis Dis. Jan 26–2018.(Epub ahead of print). doi: 10.1016/j.bbadis.2018.06.016. View Article : Google Scholar :

23 

Kato M, Wang L, Putta S, Wang M, Yuan H, Sun G, Lanting L, Todorov I, Rossi JJ and Natarajan R: Post-transcriptional up-regulation of Tsc-22 by Ybx1, a target of miR-216a, mediates TGF-{beta}-induced collagen expression in kidney cells. J Biol Chem. 285:34004–34015. 2010. View Article : Google Scholar : PubMed/NCBI

24 

National Research Council (US) Institute for Laboratory Animal Research, . Guide for the care and use of laboratory animals. National Academies Press; 1996

25 

O'Connell TD, Rodrigo MC and Simpson PC: Isolation and culture of adult mouse cardiac myocytes. Methods Mol Biol. 357:271–296. 2007.PubMed/NCBI

26 

Geyer FC, Li A, Papanastasiou AD, Smith A, Selenica P, Burke KA, Edelweiss M, Wen HC, Piscuoglio S, Schultheis AM, et al: Recurrent hotspot mutations in HRAS Q61 and PI3K-AKT pathway genes as drivers of breast adenomyoepitheliomas. Nat Commun. 9:18162018. View Article : Google Scholar : PubMed/NCBI

27 

Zhang X, Ma ZG, Yuan YP, Xu SC, Wei WY, Song P, Kong CY, Deng W and Tang QZ: Rosmarinic acid attenuates cardiac fibrosis following long-term pressure overload via AMPKα/Smad3 signaling. Cell Death Dis. 9:1022018. View Article : Google Scholar : PubMed/NCBI

28 

Ma ZG, Yuan YP, Xu SC, Wei WY, Xu CR, Zhang X, Wu QQ, Liao HH, Ni J and Tang QZ: CTRP3 attenuates cardiac dysfunction, inflammation, oxidative stress and cell death in diabetic cardiomyopathy in rats. Diabetologia. 60:1126–1137. 2017. View Article : Google Scholar : PubMed/NCBI

29 

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

30 

Ma ZG, Dai J, Yuan YP, Bian ZY, Xu SC, Jin YG, Zhang X and Tang QZ: T-bet deficiency attenuates cardiac remodelling in rats. Basic Res Cardiol. 113:192018. View Article : Google Scholar : PubMed/NCBI

31 

Agarwal V, Bell GW, Nam JW and Bartel DP: Predicting effective microRNA target sites in mammalian mRNAs. Elife. Aug 12–2015.(Epub ahead of print). doi: 10.7554/eLife.05005. 2015. View Article : Google Scholar

32 

Lal H, Ahmad F, Zhou J, Yu JE, Vagnozzi RJ, Guo Y, Yu D, Tsai EJ, Woodgett J, Gao E and Force T: Cardiac fibroblast glycogen synthase kinase-3β regulates ventricular remodeling and dysfunction in ischemic heart. Circulation. 130:419–430. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN, Geng H, Qiu YH, von Minden MD, Ernst T, Hochhaus A, et al: PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med. 22:379–387. 2016. View Article : Google Scholar : PubMed/NCBI

34 

Lee AA, Dillmann WH, McCulloch AD and Villarreal FJ: Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J Mol Cell Cardiol. 27:2347–2357. 1995. View Article : Google Scholar : PubMed/NCBI

35 

Shirakawa K, Endo J, Kataoka M, Katsumata Y, Yoshida N, Yamamoto T, Isobe S, Moriyama H, Goto S, Kitakata H, et al: IL (Interleukin)-10-STAT3-galectin-3 axis is essential for osteopontin-producing reparative macrophage polarization after myocardial infarction. Circulation. 138:2021–2035. 2018. View Article : Google Scholar : PubMed/NCBI

36 

Horckmans M, Ring L, Duchene J, Santovito D, Schloss MJ, Drechsler M, Weber C, Soehnlein O and Steffens S: Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J. 38:187–197. 2017.PubMed/NCBI

37 

Ma ZG, Zhang X, Yuan YP, Jin YG, Li N, Kong CY, Song P and Tang QZ: A77 1726 (leflunomide) blocks and reverses cardiac hypertrophy and fibrosis in mice. Clin Sci (Lond). 132:685–699. 2018. View Article : Google Scholar : PubMed/NCBI

38 

Bottinger EP, Jakubczak JL, Roberts IS, Mumy M, Hemmati P, Bagnall K, Merlino G and Wakefield LM: Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas. EMBO J. 16:2621–2633. 1997. View Article : Google Scholar : PubMed/NCBI

39 

Nie X, Fan J, Li H, Yin Z, Zhao Y, Dai B, Dong N, Chen C and Wang DW: miR-217 promotes cardiac hypertrophy and dysfunction by targeting PTEN. Mol Ther Nucleic Acids. 12:254–266. 2018. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 19 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Qu, C., Liu, X., Ye, T., Wang, L., Liu, S., Zhou, X. ... Yang, B. (2019). miR‑216a exacerbates TGF‑β‑induced myofibroblast transdifferentiation via PTEN/AKT signaling. Molecular Medicine Reports, 19, 5345-5352. https://doi.org/10.3892/mmr.2019.10200
MLA
Qu, C., Liu, X., Ye, T., Wang, L., Liu, S., Zhou, X., Wu, G., Lin, J., Shi, S., Yang, B."miR‑216a exacerbates TGF‑β‑induced myofibroblast transdifferentiation via PTEN/AKT signaling". Molecular Medicine Reports 19.6 (2019): 5345-5352.
Chicago
Qu, C., Liu, X., Ye, T., Wang, L., Liu, S., Zhou, X., Wu, G., Lin, J., Shi, S., Yang, B."miR‑216a exacerbates TGF‑β‑induced myofibroblast transdifferentiation via PTEN/AKT signaling". Molecular Medicine Reports 19, no. 6 (2019): 5345-5352. https://doi.org/10.3892/mmr.2019.10200