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Article

Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway

  • Authors:
    • Liman Qiu
    • Jinxiao Chen
    • Jing Lin
    • Da Wo
    • Jianfeng Chu
    • Jun Peng
  • View Affiliations / Copyright

    Affiliations: Fujian Key Laboratory of Integrative Geriatric Medicine, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China, Key Laboratory of Arrhythmias of The Ministry of Education of China, Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
  • Pages: 9251-9255
    |
    Published online on: October 10, 2017
       https://doi.org/10.3892/mmr.2017.7748
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Abstract

Baicalin is one of the active ingredients extracted from the dry root of Scutellaria baicalensis Georgi, which has been reported to be effective in preventing myocardial ischemia reperfusion injury. However, the mechanisms underlying its cardioprotective activities remain to be elucidated. In the present study, H2O2‑treated cardiomyocyte H9c2 cell line served as an in vitro model of oxidation‑damaged cardiomyocytes to evaluate the effects of baicalin on the cardiac injury, and to investigate the underlying molecular mechanism. The results of the TOPFlash/Renilla reporter gene assay indicated that baicalin significantly suppressed the activation of proto‑oncogene Wnt‑1 (Wnt)/β‑catenin in 293 cells, in a dose dependent manner. In addition, baicalin significantly inhibited H2O2‑induced loss of H9c2 cell viability in MTT assay. Furthermore, western blotting analysis demonstrated that baicalin markedly attenuated H2O2‑induced cell apoptosis, as demonstrated by the down‑regulation of cleaved caspase‑3 and the increase in the apoptosis regulator Bcl‑2 (Bcl‑2)/apoptosis regulator BAX (Bax) ratio following baicalin treatment in H2O2‑treated H9c2 cells. Furthermore, baicalin markedly decreased the expression of β‑catenin and downstream Axin‑2 and myc proto‑oncogene protein in H2O2‑treated H9c2 cells. Knockdown of β‑catenin expression inhibited H2O2‑induced cell apoptosis. Finally, LiCl (a β‑catenin stabilizer) induced apoptosis of H9c2 cells by upregulating the expression of β‑catenin, which was significantly neutralized by the treatment with baicalin. Taken together, it is hypothesized that baicalin exerts cardioprotective effects via suppression of the Wnt/β‑catenin signaling pathway.
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1 

Dohn TE and Waxman JS: Distinct phases of Wnt/β-catenin signaling direct cardiomyocyte formation in zebrafish. Dev Biol. 361:364–376. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Gessert S and Kühl M: The multiple phases and faces of wnt signaling during cardiac differentiation and development. Circ Res. 107:186–199. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Gibb N, Lavery DL and Hoppler S: Sfrp1 promotes cardiomyocyte differentiation in Xenopus via negative-feedback regulation of Wnt signalling. Development. 140:1537–1549. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Yamashita JK, Takano M, Hiraoka-Kanie M, Shimazu C, Peishi Y, Yanagi K, Nakano A, Inoue E, Kita F and Nishikawa S: Prospective identification of cardiac progenitors by a novel single cell-based cardiomyocyte induction. FASEB J. 19:1534–1536. 2005.PubMed/NCBI

5 

Barandon L, Couffinhal T, Ezan J, Dufourcq P, Costet P, Alzieu P, Leroux L, Moreau C, Dare D and Duplàa C: Reduction of infarct size and prevention of cardiac rupture in transgenic mice overexpressing FrzA. Circulation. 108:2282–2289. 2003. View Article : Google Scholar : PubMed/NCBI

6 

Mirotsou M, Zhang Z, Deb A, Zhang L, Gnecchi M, Noiseux N, Mu H, Pachori A and Dzau V: Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci USA. 104:pp. 1643–1648. 2007; View Article : Google Scholar : PubMed/NCBI

7 

Zhang Z, Deb A, Zhang Z, Pachori A, He W, Guo J, Pratt R and Dzau VJ: Secreted frizzled related protein 2 protects cells from apoptosis by blocking the effect of canonical Wnt3a. J Mol Cell Cardiol. 46:370–377. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Zhu W, Shiojima I, Ito Y, Li Z, Ikeda H, Yoshida M, Naito AT, Nishi J, Ueno H, Umezawa A, et al: IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature. 454:345–349. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Funato Y and Miki H: Redox regulation of Wnt signalling via nucleoredoxin. Free Radic Res. 44:379–388. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Kafka A, Bašić-Kinda S and Pećina-Šlaus N: The cellular story of dishevelleds. Croat Med J. 55:459–467. 2014. View Article : Google Scholar : PubMed/NCBI

11 

MacDonald BT, Tamai K and He X: Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev Cell. 17:9–26. 2009. View Article : Google Scholar : PubMed/NCBI

12 

Kong F, Luan Y, Zhang ZH, Cheng GH, Qi TG and Sun C: Baicalin protects the myocardium from reperfusion-induced damage in isolated rat hearts via the antioxidant and paracrine effect. Exp Ther Med. 7:254–259. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Xu M, Chen X, Gu Y, Peng T, Yang D, Chang RC, So KF, Liu K and Shen J: Baicalin can scavenge peroxynitrite and ameliorate endogenous peroxynitrite-mediated neurotoxicity in cerebral ischemia-reperfusion injury. J Ethnopharmacol. 150:116–124. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Liu X, Gu J, Fan Y, Shi H and Jiang M: Baicalin attenuates acute myocardial infarction of rats via mediating the mitogen-activated protein kinase pathway. Biol Pharm Bull. 36:988–994. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Sun SJ, Wu XP, Song HL and Li GQ: Baicalin ameliorates isoproterenol-induced acute myocardial infarction through iNOS, inflammation, oxidative stress and P38MAPK pathway in rat. Int J Clin Exp Med. 8:22063–22072. 2015.PubMed/NCBI

16 

Zhang J, Liu S, Xu B, Li G, Li G, Huang A, Wu B, Peng L, Song M, Xie Q, et al: Study of baicalin on sympathoexcitation induced by myocardial ischemia via P2X3 receptor in superior cervical ganglia. Auton Neurosci. 189:8–15. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Shen M, Wang L, Yang G, Gao L, Wang B, Guo X, Zeng C, Xu Y, Shen L, Cheng K, et al: Baicalin protects the cardiomyocytes from ER stress-induced apoptosis: Inhibition of CHOP through induction of endothelial nitric oxide synthase. PLoS One. 9:e883892014. View Article : Google Scholar : PubMed/NCBI

18 

Berg K, Jynge P, Bjerve K, Skarra S, Basu S and Wiseth R: Oxidative stress and inflammatory response during and following coronary interventions for acute myocardial infarction. Free Radic Res. 39:629–636. 2005. View Article : Google Scholar : PubMed/NCBI

19 

Sun Y: Myocardial repair/remodelling following infarction: Roles of local factors. Cardiovasc Res. 81:482–490. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Diestel A, Drescher C, Miera O, Berger F and Schmitt KR: Hypothermia protects H9c2 cardiomyocytes from H2O2 induced apoptosis. Cryobiology. 62:53–61. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Eguchi M, Liu Y, Shin EJ and Sweeney G: Leptin protects H9c2 rat cardiomyocytes from H2O2-induced apoptosis. FEBS J. 275:3136–3144. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Law CH, Li JM, Chou HC, Chen YH and Chan HL: Hyaluronic acid-dependent protection in H9C2 cardiomyocytes: A cell model of heart ischemia-reperfusion injury and treatment. Toxicology. 303:54–71. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Park ES, Kang JC, Jang YC, Park JS, Jang SY, Kim DE, Kim B and Shin HS: Cardioprotective effects of rhamnetin in H9c2 cardiomyoblast cells under H2 O2 -induced apoptosis. J Ethnopharmacol. 153:552–560. 2014. View Article : Google Scholar : PubMed/NCBI

24 

Chen J, Yan H, Ren DN, Yin Y, Li Z, He Q, Wo D, Ho MS, Chen Y, Liu Z, et al: LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation. Cell Signal. 26:1068–1074. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C, et al: Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature. 417:664–667. 2002. View Article : Google Scholar : PubMed/NCBI

26 

Mao B, Wu W, Li Y, Hoppe D, Stannek P, Glinka A and Niehrs C: LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature. 411:321–325. 2001. View Article : Google Scholar : PubMed/NCBI

27 

Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP and He X: LDL-receptor-related proteins in Wnt signal transduction. Nature. 407:530–535. 2000. View Article : Google Scholar : PubMed/NCBI

28 

Veeman MT, Slusarski DC, Kaykas A, Louie SH and Moon RT: Zebrafish prickle, a modulator of noncanonical Wnt/Fz signaling, regulates gastrulation movements. Curr Biol. 13:680–685. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Ren DN, Chen J, Li Z, Yan H, Yin Y, Wo D, Zhang J, Ao L, Chen B, Ito TK, et al: LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis. Nat Commun. 6:69062015. View Article : Google Scholar : PubMed/NCBI

30 

Caraci F, Gili E, Calafiore M, Failla M, La Rosa C, Crimi N, Sortino MA, Nicoletti F, Copani A and Vancheri C: TGF-beta1 targets the GSK-3beta/beta-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts. Pharmacol Res. 57:274–282. 2008. View Article : Google Scholar : PubMed/NCBI

31 

Wang Y, Lam JB, Lam KS, Liu J, Lam MC, Hoo RL, Wu D, Cooper GJ and Xu A: Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice. Cancer Res. 66:11462–11470. 2006. View Article : Google Scholar : PubMed/NCBI

32 

Zhang Y, Qiu WJ, Liu DX, Neo SY, He X and Lin SC: Differential molecular assemblies underlie the dual function of Axin in modulating the WNT and JNK pathways. J Biol Chem. 276:32152–32159. 2001. View Article : Google Scholar : PubMed/NCBI

33 

Funato Y, Michiue T, Asashima M and Miki H: The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Nat Cell Biol. 8:501–508. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Wo D, Peng J, Ren DN, Qiu L, Chen J, Zhu Y, Yan Y, Yan H, Wu J, Ma E, et al: Opposing roles of Wnt inhibitors IGFBP-4 and Dkk1 in cardiac ischemia by differential targeting of LRP5/6 and β-catenin. Circulation. 134:1991–2007. 2016. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Qiu L, Chen J, Lin J, Wo D, Chu J and Peng J: Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway. Mol Med Rep 16: 9251-9255, 2017.
APA
Qiu, L., Chen, J., Lin, J., Wo, D., Chu, J., & Peng, J. (2017). Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway. Molecular Medicine Reports, 16, 9251-9255. https://doi.org/10.3892/mmr.2017.7748
MLA
Qiu, L., Chen, J., Lin, J., Wo, D., Chu, J., Peng, J."Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway". Molecular Medicine Reports 16.6 (2017): 9251-9255.
Chicago
Qiu, L., Chen, J., Lin, J., Wo, D., Chu, J., Peng, J."Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway". Molecular Medicine Reports 16, no. 6 (2017): 9251-9255. https://doi.org/10.3892/mmr.2017.7748
Copy and paste a formatted citation
x
Spandidos Publications style
Qiu L, Chen J, Lin J, Wo D, Chu J and Peng J: Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway. Mol Med Rep 16: 9251-9255, 2017.
APA
Qiu, L., Chen, J., Lin, J., Wo, D., Chu, J., & Peng, J. (2017). Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway. Molecular Medicine Reports, 16, 9251-9255. https://doi.org/10.3892/mmr.2017.7748
MLA
Qiu, L., Chen, J., Lin, J., Wo, D., Chu, J., Peng, J."Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway". Molecular Medicine Reports 16.6 (2017): 9251-9255.
Chicago
Qiu, L., Chen, J., Lin, J., Wo, D., Chu, J., Peng, J."Baicalin alleviates H2O2‑induced injury of H9c2 cardiomyocytes through suppression of the Wnt/β‑catenin signaling pathway". Molecular Medicine Reports 16, no. 6 (2017): 9251-9255. https://doi.org/10.3892/mmr.2017.7748
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