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Scutellarein protects against cardiac hypertrophy via suppressing TRAF2/NF-κB signaling pathway

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Abstract

Background

Scutellarein, a widely studied ingredient of scutellaria herbs, has higher bioavailability and solubility than that of scutellarin. Although the scutellarein had been reported to modulate numerous biological functions, its ability in suppressing cardiac hypertrophy remains unclear. Hence, the present study attempted to investigate whether scutellarein played critical roles in preventing phenylephrine (PE)-induced cardiac hypertrophy.

Methods and results

Immunocytochemistry (ICC) was employed for evaluating the morphology of the treated cardiomyocytes. Real-time PCR and western blot were respectively applied to assess the mRNA levels and protein expression of the relevant molecules. Bioinformatics analyses were carried out to investigate the potential mechanisms by which scutellarein modulated the PE-induced cardiac hypertrophy. The results showed that Scutellarein treatment significantly inhibited PE-induced increase in H9c2 and AC16 cardiomyocyte size. Besides, scutellarein treatment also dramatically suppressed the expression of the cardiac hypertrophic markers: ANP, BNP and β-MHC. Furthermore, the effects of scutellarein on attenuating the cardiac hypertrophy might be mediated by suppressing the activity of TRAF2/NF-κB signaling pathway.

Conclusions

Collectively, our data indicated that scutellarein could protect against PE-induced cardiac hypertrophy via regulating TRAF2/NF-κB signaling pathway using in vitro experiments.

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Data availability

The data and materials are available on reasonable request.

References

  1. Gupta S, Das B, Sen S (2007) Cardiac hypertrophy: mechanisms and therapeutic opportunities. Antioxid Redox Signal 9:623–652. https://doi.org/10.1089/ars.2007.1474

    Article  CAS  PubMed  Google Scholar 

  2. Devereux RB, Roman MJ (1999) Left ventricular hypertrophy in hypertension: stimuli, patterns, and consequences. Hypertens Res 22:1–9. https://doi.org/10.1291/hypres.22.1

    Article  CAS  PubMed  Google Scholar 

  3. Xia Y, Karmazyn M (2004) Obligatory role for endogenous endothelin in mediating the hypertrophic effects of phenylephrine and angiotensin II in neonatal rat ventricular myocytes: evidence for two distinct mechanisms for endothelin regulation. J Pharmacol Exp Ther 310:43–51. https://doi.org/10.1124/jpet.104.065185

    Article  CAS  PubMed  Google Scholar 

  4. Frey N, Olson EN (2003) Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65:45–79. https://doi.org/10.1146/annurev.physiol.65.092101.142243

    Article  CAS  PubMed  Google Scholar 

  5. Bisping E, Wakula P, Poteser M, Heinzel FR (2014) Targeting cardiac hypertrophy: toward a causal heart failure therapy. J Cardiovasc Pharmacol 64:293–305. https://doi.org/10.1097/FJC.0000000000000126

    Article  CAS  PubMed  Google Scholar 

  6. Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR (2015) Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets. Arch Toxicol 89:1401–1438. https://doi.org/10.1007/s00204-015-1477-x

    Article  CAS  PubMed  Google Scholar 

  7. Devin A, Lin Y, Yamaoka S, Li Z, Karin M, Liu Z (2001) The alpha and beta subunits of IkappaB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. Mol Cell Biol 21:3986–3994. https://doi.org/10.1128/MCB.21.12.3986-3994.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu SF, Malik AB (2006) NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 290:L622–L645. https://doi.org/10.1152/ajplung.00477.2005

    Article  CAS  PubMed  Google Scholar 

  9. Kuusisto J, Karja V, Sipola P, Kholova I, Peuhkurinen K, Jaaskelainen P, Naukkarinen A, Yla-Herttuala S, Punnonen K, Laakso M (2012) Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy. Heart 98:1007–1013. https://doi.org/10.1136/heartjnl-2011-300960

    Article  PubMed  Google Scholar 

  10. Barnes PJ, Karin M (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:1066–1071. https://doi.org/10.1056/NEJM199704103361506

    Article  CAS  PubMed  Google Scholar 

  11. Baeuerle PA, Baltimore D (1996) NF-kappa B: ten years after. Cell 87:13–20. https://doi.org/10.1016/s0092-8674(00)81318-5

    Article  CAS  PubMed  Google Scholar 

  12. Wang Z, Gao L, Xiao L, Kong L, Shi H, Tian X, Zhao L (2018) Bakuchiol protects against pathological cardiac hypertrophy by blocking NF-kappaB signaling pathway. Biosci Rep. https://doi.org/10.1042/BSR20181043

    Article  PubMed  PubMed Central  Google Scholar 

  13. Manna SK, Babajan B, Raghavendra PB, Raviprakash N, Sureshkumar C (2010) Inhibiting TRAF2-mediated activation of NF-kappaB facilitates induction of AP-1. J Biol Chem 285:11617–11627. https://doi.org/10.1074/jbc.M109.094961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Su D, Cheng Y, Li S, Dai D, Zhang W, Lv M (2017) Sphk1 mediates neuroinflammation and neuronal injury via TRAF2/NF-kappaB pathways in activated microglia in cerebral ischemia reperfusion. J Neuroimmunol 305:35–41. https://doi.org/10.1016/j.jneuroim.2017.01.015

    Article  CAS  PubMed  Google Scholar 

  15. Gao R, Zhu BH, Tang SB, Wang JF, Ren J (2008) Scutellarein inhibits hypoxia- and moderately-high glucose-induced proliferation and VEGF expression in human retinal endothelial cells. Acta Pharmacol Sin 29:707–712. https://doi.org/10.1111/j.1745-7254.2008.00797.x

    Article  CAS  PubMed  Google Scholar 

  16. Li NG, Song SL, Shen MZ, Tang YP, Shi ZH, Tang H, Shi QP, Fu YF, Duan JA (2012) Mannich bases of scutellarein as thrombin-inhibitors: design, synthesis, biological activity and solubility. Bioorg Med Chem 20:6919–6923. https://doi.org/10.1016/j.bmc.2012.10.015

    Article  CAS  PubMed  Google Scholar 

  17. Sang Eun H, Seong Min K, Ho Jeong L, Vetrivel P, Venkatarame Gowda Saralamma V, Jeong Doo H, Eun Hee K, Sang Joon L, Sup K (2019) Scutellarein induces fas-mediated extrinsic apoptosis and G2/M cell cycle arrest in Hep3B hepatocellular carcinoma cells. Nutrients. https://doi.org/10.3390/nu11020263

    Article  PubMed  Google Scholar 

  18. Tang H, Tang Y, Li N, Shi Q, Guo J, Shang E, Duan JA (2014) Neuroprotective effects of scutellarin and scutellarein on repeatedly cerebral ischemia-reperfusion in rats. Pharmacol Biochem Behav 118:51–59. https://doi.org/10.1016/j.pbb.2014.01.003

    Article  CAS  PubMed  Google Scholar 

  19. Zhou J, Lei H, Chen Y, Li F, Ma C (2002) Ventricular remodeling by Scutellarein treatment in spontaneously hypertensive rats. Chin Med J (Engl) 115:375–377

    Google Scholar 

  20. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322:1561–1566. https://doi.org/10.1056/NEJM199005313222203

    Article  CAS  PubMed  Google Scholar 

  21. Stoclet JC, Schini-Kerth V (2011) Dietary flavonoids and human health. Ann Pharm Fr 69:78–90. https://doi.org/10.1016/j.pharma.2010.11.004

    Article  CAS  PubMed  Google Scholar 

  22. Yan L, Huang H, Tang QZ, Zhu LH, Wang L, Liu C, Bian ZY, Li H (2010) Breviscapine protects against cardiac hypertrophy through blocking PKC-alpha-dependent signaling. J Cell Biochem 109:1158–1171. https://doi.org/10.1002/jcb.22495

    Article  CAS  PubMed  Google Scholar 

  23. Xing JF, You HS, Dong YL, Lu J, Chen SY, Zhu HF, Dong Q, Wang MY, Dong WH (2011) Metabolic and pharmacokinetic studies of scutellarin in rat plasma, urine, and feces. Acta Pharmacol Sin 32:655–663. https://doi.org/10.1038/aps.2011.11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. You HS, Xing JF, Lu J, Dong WH, Liu JT, Dong YL (2014) Influence of the gastrointestinal microflora and efflux transporters on the absorption of scutellarin and scutellarein. Phytother Res 28:1295–1300. https://doi.org/10.1002/ptr.5127

    Article  CAS  PubMed  Google Scholar 

  25. Feng MQ, Song YH, Wu JX, Chen X, Bai XH, Zhang YQ (2017) Study on antitumour activity of scutellarin and its metabolite scutellarein by combining activity screening, target tissue distribution and pharmacokinetics. Chromatographia 80:427–435. https://doi.org/10.1007/s10337-017-3260-z

    Article  CAS  Google Scholar 

  26. Bogoyevitch MA, Glennon PE, Sugden PH (1993) Endothelin-1, phorbol esters and phenylephrine stimulate MAP kinase activities in ventricular cardiomyocytes. FEBS Lett 317:271–275. https://doi.org/10.1016/0014-5793(93)81291-7

    Article  CAS  PubMed  Google Scholar 

  27. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH (1998) The low molecular weight GTPase Rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of Rho kinase. J Biol Chem 273:7725–7730. https://doi.org/10.1074/jbc.273.13.7725

    Article  CAS  PubMed  Google Scholar 

  28. Valen G, Yan ZQ, Hansson GK (2001) Nuclear factor kappa-B and the heart. J Am Coll Cardiol 38:307–314. https://doi.org/10.1016/s0735-1097(01)01377-8

    Article  CAS  PubMed  Google Scholar 

  29. Saito T, Tanaka S (2017) Molecular mechanisms underlying osteoarthritis development: Notch and NF-kappaB. Arthritis Res Ther 19:94. https://doi.org/10.1186/s13075-017-1296-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388:548–554. https://doi.org/10.1038/41493

    Article  CAS  PubMed  Google Scholar 

  31. Baldwin AS Jr (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14:649–683. https://doi.org/10.1146/annurev.immunol.14.1.649

    Article  CAS  PubMed  Google Scholar 

  32. Thurberg BL, Collins T (1998) The nuclear factor-kappa B/inhibitor of kappa B autoregulatory system and atherosclerosis. Curr Opin Lipidol 9:387–396. https://doi.org/10.1097/00041433-199810000-00002

    Article  CAS  PubMed  Google Scholar 

  33. Etemadi N, Chopin M, Anderton H, Tanzer MC, Rickard JA, Abeysekera W, Hall C, Spall SK, Wang B, Xiong Y, Hla T, Pitson SM, Bonder CS, Wong WW, Ernst M, Smyth GK, Vaux DL, Nutt SL, Nachbur U, Silke J (2015) TRAF2 regulates TNF and NF-kappaB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife. https://doi.org/10.7554/eLife.10592

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pomerantz JL, Baltimore D (1999) NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J 18:6694–6704. https://doi.org/10.1093/emboj/18.23.6694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yamamoto S, Iwakuma T (2017) RIPK1-TRAF2 interplay on the TNF/NF-kappaB signaling, cell death, and cancer development in the liver. Transl Cancer Res 6:94–109. https://doi.org/10.21037/tcr.2017.04.01

    Article  CAS  PubMed  Google Scholar 

  36. Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A, de la Pompa JL, Ferrick D, Hum B, Iscove N, Ohashi P, Rothe M, Goeddel DV, Mak TW (1997) Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7:715–725. https://doi.org/10.1016/s1074-7613(00)80391-x

    Article  CAS  PubMed  Google Scholar 

  37. Huang Y, Wu D, Zhang X, Jiang M, Hu C, Lin J, Tang J, Wu L (2014) Cardiac-specific Traf2 overexpression enhances cardiac hypertrophy through activating AKT/GSK3beta signaling. Gene 536:225–231. https://doi.org/10.1016/j.gene.2013.12.052

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Science and Technology Commission of Shanghai Municipality (NO. 19DZ2201000) and the Outstanding Clinical Discipline Project of Shanghai Pudong (No.: PWYgy2018-10).

Funding

This work was supported by Science and Technology Commission of Shanghai Municipality (19DZ2201000) and the Outstanding Clinical Discipline Project of Shanghai Pudong (PWYgy2018-10).

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Author notes

  1. Xiujuan Shi, Yongjia Hu and Yuxiong Jiang contributed equally.

Authors and Affiliations

  1. School of Medicine, Tongji University, Shanghai, China

    Xiujuan Shi, Yongjia Hu, Yuxiong Jiang, Jiawen Wu, Chen Zhang, Jieping Zhang, Shengyu Wu, Yingshi Wu, Weibing Dong & Jue Li

  2. Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai, China

    Jue Li

  3. Shanghai East Hospital, Tongji University School of Medicine, 1239 Siping Road, Shanghai, 200092, China

    Jue Li

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Contributions

XS and JL conceived the study. XS, YH and YJ wrote the paper. XS, YH, YJ, JW, SW, YW, WD, CZ, JZ performed the experiments and the data analysis.

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Correspondence to Jue Li.

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Shi, X., Hu, Y., Jiang, Y. et al. Scutellarein protects against cardiac hypertrophy via suppressing TRAF2/NF-κB signaling pathway. Mol Biol Rep 49, 2085–2095 (2022). https://doi.org/10.1007/s11033-021-07026-0

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