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Article

Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway

  • Authors:
    • Guiqiong Huang
    • Xiaofang Huang
    • Min Liu
    • Yue Hua
    • Bo Deng
    • Wen Jin
    • Wen Yan
    • Zhangbin Tan
    • Yifen Wu
    • Bin Liu
    • Yingchun Zhou
  • View Affiliations / Copyright

    Affiliations: School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
  • Pages: 3570-3576
    |
    Published online on: March 13, 2018
       https://doi.org/10.3892/ijmm.2018.3560
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Abstract

Myocardial cell apoptosis mediated by oxidative stress has previously been identified as a key process in ischemic heart disease. Secoisolariciresinol diglucoside (SDG), a polyphenolic plant lignan primarily found in flaxseed, has been demonstrated to effectively protect myocardial cells from apoptosis. In the present study, the role of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) was investigated in mediating the protective effect of SDG. Findings of the present study revealed that treatment with H2O2 reduced cell viability and induced apoptosis in H9C2 rat cardiomyocytes. However, SDG was able to reduce the effect of H2O2 in a dose‑dependent manner. H2O2 reduced the expression level of phosphorylated STAT3 and inhibited the levels of B‑cell lymphoma‑extra‑large and induced myeloid leukemia cell differentiation protein, which are the STAT3 target genes. Conversely, SDG rescued phosphorylation of STAT3 and increased the levels of STAT3 target genes. Treatment with SDG alone led to a dose‑dependent increased phosphorylation of JAK2 and STAT3, without activating Src. Furthermore, the anti‑apoptotic effects of SDG were partially abolished by a JAK2/STAT3 inhibitor. In addition, molecular docking revealed that SDG may bind to the protein kinase domain of JAK2, at a binding energy of ‑8.258 kcal/mol. Molecular dynamics simulations revealed that JAK2‑SDG binding was stable. In conclusion, activation of the JAK2/STAT3 signaling pathway contributed to the anti‑apoptotic activity of SDG, which may be a potential JAK2 activator.
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View References

1 

Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, et al: Heart disease and stroke statistics-2017 update: A report from the American heart association. Circulation. 135:e146–e603. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Singh SS and Kang PM: Mechanisms and inhibitors of apoptosis in cardiovascular diseases. Curr Pharm Des. 17:1783–1793. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Zhao ZQ: Oxidative stress-elicited myocardial apoptosis during reperfusion. Curr Opin Pharmacol. 4:159–165. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Hamacher-Brady A, Brady NR and Gottlieb RA: The interplay between pro-death and pro-survival signaling pathways in myocardial ischemia/reperfusion injury: Apoptosis meets autophagy. Cardiovasc Drugs Ther. 20:445–462. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Slavova-Kazakova A, Karamać M, Kancheva V and Amarowicz R: Antioxidant activity of flaxseed extracts in lipid systems. Molecules. 21:E172015. View Article : Google Scholar : PubMed/NCBI

6 

Prasad K and Dhar A: Flaxseed and diabetes. Curr Pharm Des. 22:141–144. 2016. View Article : Google Scholar

7 

Prasad K: Flaxseed and cardiovascular health. J Cardiovasc Pharmacol. 54:369–377. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Penumathsa SV, Koneru S, Thirunavukkarasu M, Zhan L, Prasad K and Maulik N: Secoisolariciresinol diglucoside: Relevance to angiogenesis and cardioprotection against ischemia-reperfusion injury. J Pharmacol Exp Ther. 320:951–959. 2007. View Article : Google Scholar

9 

Penumathsa SV, Koneru S, Zhan L, John S, Menon VP, Prasad K and Maulik N: Secoisolariciresinol diglucoside induces neovascularization-mediated cardioprotection against ischemia-reperfusion injury in hypercholesterolemic myocardium. J Mol Cell Cardiol. 44:170–179. 2008. View Article : Google Scholar

10 

Puukila S, Bryan S, Laakso A, Abdel-Malak J, Gurney C, Agostino A, Belló-Klein A, Prasad K and Khaper N: Secoisolariciresinol diglucoside abrogates oxidative stress-induced damage in cardiac iron overload condition. PLoS One. 10:e1228522015. View Article : Google Scholar

11 

Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G and Schulz R: The myocardial JAK/STAT pathway: From protection to failure. Pharmacol Ther. 120:172–185. 2008. View Article : Google Scholar : PubMed/NCBI

12 

Bolli R, Stein AB, Guo Y, Wang OL, Rokosh G, Dawn B, Molkentin JD, Sanganalmath SK, Zhu Y and Xuan YT: A murine model of inducible, cardiac-specific deletion of STAT3: Its use to determine the role of STAT3 in the upregulation of cardioprotective proteins by ischemic preconditioning. J Mol Cell Cardiol. 50:589–597. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Xuan YT, Guo Y, Han H, Zhu Y and Bolli R: An essential role of the JAK-STAT pathway in ischemic preconditioning. Proc Natl Acad Sci USA. 98:9050–9055. 2001. View Article : Google Scholar : PubMed/NCBI

14 

Suleman N, Somers S, Smith R, Opie LH and Lecour SC: Dual activation of STAT-3 and Akt is required during the trigger phase of ischaemic preconditioning. Cardiovasc Res. 79:127–133. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, Hillmer A, Schmiedl A, Ding Z, Podewski E, et al: Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res. 95:187–195. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Jacoby JJ, Kalinowski A, Liu MG, Zhang SS, Gao Q, Chai GX, Ji L, Iwamoto Y, Li E, Schneider M, et al: Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci USA. 100:12929–12934. 2003. View Article : Google Scholar : PubMed/NCBI

17 

Liu B, Zhang J, Liu W, Liu N, Fu X, Kwan H and Liu S, Liu B, Zhang S, Yu Z and Liu S: Calycosin inhibits oxidative stress-induced cardiomyocyte apoptosis via activating estrogen receptor-α/β. Bioorg Med Chem Lett. 26:181–185. 2016. View Article : Google Scholar

18 

Liu B, Liu NN, Liu WH, Zhang SW, Zhang JZ, Li AQ and Liu SM: Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 reduces cardiac fibroblast proliferation by suppressing GATA binding protein 4. Biochem Biophys Res Commun. 475:329–334. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Su Q, Ioannidis S, Chuaqui C, Almeida L, Alimzhanov M, Bebernitz G, Bell K, Block M, Howard T, Huang S, et al: Discovery of 1-methyl-1H-imidazole derivatives as potent Jak2 inhibitors. J Med Chem. 57:144–158. 2014. View Article : Google Scholar

20 

Trott O and Olson AJ: AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 31:455–461. 2010.

21 

Yang Y, Hu B and Lill MA: WATsite2.0 with PyMOL Plugin: Hydration site prediction and visualization. Methods Mol Biol. 1611:123–134. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Laskowski RA and Swindells MB: LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model. 51:2778–2786. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Krieger E, Koraimann G and Vriend G: Increasing the precision of comparative models with YASARA NOVA-a self-parameterizing force field. Proteins. 47:393–402. 2002. View Article : Google Scholar : PubMed/NCBI

24 

Teng Y, Ross JL and Cowell JK: The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT. 3:e280862014.PubMed/NCBI

25 

Nam S, Xie J, Perkins A, Ma Y, Yang F, Wu J, Wang Y, Xu RZ, Huang W, Horne DA and Jove R: Novel synthetic derivatives of the natural product berbamine inhibit Jak2/Stat3 signaling and induce apoptosis of human melanoma cells. Mol Oncol. 6:484–493. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Niu G, Bowman T, Huang M, Shivers S, Reintgen D, Daud A, Chang A, Kraker A, Jove R and Yu H: Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene. 21:7001–7010. 2002. View Article : Google Scholar : PubMed/NCBI

27 

Song B, Jin H, Yu X, Zhang Z, Yu H, Ye J, Xu Y, Zhou T, Oudit GY, Ye JY, et al: Angiotensin-converting enzyme 2 attenuates oxidative stress and VSMC proliferation via the JAK2/STAT3/SOCS3 and profilin-1/MAPK signaling pathways. Regul Pept. 185:44–51. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Podewski EK, Hilfiker-Kleiner D, Hilfiker A, Morawietz H, Lichtenberg A, Wollert KC and Drexler H: Alterations in Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy. Circulation. 107:798–802. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Zhang W, Qu X, Chen B, Snyder M, Wang M, Li B, Tang Y, Chen H, Zhu W, Zhan L, et al: Critical roles of STAT3 in β-adrenergic functions in the heart. Circulation. 133:48–61. 2016. View Article : Google Scholar

30 

Reed DK and Arany I: Sex hormones differentially modulate STAT3-dependent antioxidant responses during oxidative stress in renal proximal tubule cells. In Vivo. 28:1097–1100. 2014.PubMed/NCBI

31 

Carpenter RL and Lo HW: STAT3 target genes relevant to human cancers. Cancers (Basel). 6:897–925. 2014. View Article : Google Scholar

32 

Chen-Scarabelli C, Saravolatz IL, McCaukey R, Scarabelli G, Di Rezze J, Mohanty B, Barry S, Latchman D, Georgiadis V, McCormick J, et al: The cardioprotective effects of urocortin are mediated via activation of the Src tyrosine kinase-STAT3 pathway. JAKSTAT. 2:e248122013.

33 

Czemplik M, Kulma A, Bazela K and Szopa J: The biomedical potential of genetically modified flax seeds overexpressing the glucosyltransferase gene. BMC Complement Altern Med. 12:2512012. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Huang G, Huang X, Liu M, Hua Y, Deng B, Jin W, Yan W, Tan Z, Wu Y, Liu B, Liu B, et al: Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway. Int J Mol Med 41: 3570-3576, 2018.
APA
Huang, G., Huang, X., Liu, M., Hua, Y., Deng, B., Jin, W. ... Zhou, Y. (2018). Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway. International Journal of Molecular Medicine, 41, 3570-3576. https://doi.org/10.3892/ijmm.2018.3560
MLA
Huang, G., Huang, X., Liu, M., Hua, Y., Deng, B., Jin, W., Yan, W., Tan, Z., Wu, Y., Liu, B., Zhou, Y."Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway". International Journal of Molecular Medicine 41.6 (2018): 3570-3576.
Chicago
Huang, G., Huang, X., Liu, M., Hua, Y., Deng, B., Jin, W., Yan, W., Tan, Z., Wu, Y., Liu, B., Zhou, Y."Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway". International Journal of Molecular Medicine 41, no. 6 (2018): 3570-3576. https://doi.org/10.3892/ijmm.2018.3560
Copy and paste a formatted citation
x
Spandidos Publications style
Huang G, Huang X, Liu M, Hua Y, Deng B, Jin W, Yan W, Tan Z, Wu Y, Liu B, Liu B, et al: Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway. Int J Mol Med 41: 3570-3576, 2018.
APA
Huang, G., Huang, X., Liu, M., Hua, Y., Deng, B., Jin, W. ... Zhou, Y. (2018). Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway. International Journal of Molecular Medicine, 41, 3570-3576. https://doi.org/10.3892/ijmm.2018.3560
MLA
Huang, G., Huang, X., Liu, M., Hua, Y., Deng, B., Jin, W., Yan, W., Tan, Z., Wu, Y., Liu, B., Zhou, Y."Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway". International Journal of Molecular Medicine 41.6 (2018): 3570-3576.
Chicago
Huang, G., Huang, X., Liu, M., Hua, Y., Deng, B., Jin, W., Yan, W., Tan, Z., Wu, Y., Liu, B., Zhou, Y."Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway". International Journal of Molecular Medicine 41, no. 6 (2018): 3570-3576. https://doi.org/10.3892/ijmm.2018.3560
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