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Rhodiola crenulata reduces ventricular arrhythmia through mitigating the activation of IL-17 and inhibiting the MAPK signaling pathway

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Abstract

Purpose

Ventricular arrhythmia (VA) is related to inflammatory activity. Rhodiola crenulate (RC) and its main active component, salidroside, have been reported as anti-inflammatory agents. The aim of this study was to demonstrate the effect of RC and salidroside in preventing VA via the inhibition of IL-17 in an ischemic heart failure (HF) model.

Methods

Rabbit HF models were established by coronary artery ligation for 4 weeks. These rabbits were treated with RC (125, 250, 500 mg/kg) and salidroside (9.5 mg/kg) once every 2 days for 4 weeks. WBC, serum biochemistry, ECG, and the expression of CD4+ T cells were measured every 2 weeks. The mRNA and protein expressions of IL-17 were measured by real time-PCR, ELISA, and Western blotting after RC and salidroside treatment for 4 weeks. Open-chest epicardial catheter stimulation was performed for VA provocation.

Results

After RC and salidroside treatment in HF left ventricle, (1) the levels of WBC and CD4+ T cells decreased, (2) the expression of IL-17 and its downstream target genes, IL-6, TNF-α, IL-1β, IL-8, and CCL20, reduced, (3) the level of NLRP3 inflammasome was decreased, (4) fibrosis and collagen production were significantly downregulated, (5) p38 MAPK and ERK1/2 phosphorylation were attenuated, (6) the inducibility of VA was decreased, and (7) the levels of Kir2.1, Nav1.5, NCX, PLB, SERCA2a and RyR were up-regulated.

Conclusions

RC inhibited the expression of IL-17 and its downstream target genes that were mediated by activation of several MAPKs, which decreased the levels of fibrosis and apoptosis and suppressed VA.

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References

  1. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation. 1998;98(21):2334–51.

    Article  CAS  Google Scholar 

  2. De Jesus NM, Wang L, Herren AW, Wang J, Shenasa F, Bers DM, et al. Atherosclerosis exacerbates arrhythmia following myocardial infarction: role of myocardial inflammation. Heart Rhythm. 2015;12(1):169–78.

    Article  Google Scholar 

  3. Carrick D, Haig C, Rauhalammi S, Ahmed N, Mordi I, McEntegart M, et al. Pathophysiology of LV remodeling in survivors of STEMI: inflammation, remote myocardium, and prognosis. JACC Cardiovasc Imaging. 2015;8(7):779–89.

    Article  Google Scholar 

  4. Dahiya R, Shultz SP, Dahiya A, Fu J, Flatley C, Duncan D, et al. Relation of reduced preclinical left ventricular diastolic function and cardiac remodeling in overweight youth to insulin resistance and inflammation. Am J Cardiol. 2015;115(9):1222–8.

    Article  CAS  Google Scholar 

  5. Moro-Garcia MA, Lopez Iglesias F, Avanzas P, Echeverria A, Lopez-Larrea C, Moris de la Tassa C, et al. Disease complexity in acute coronary syndrome is related to the patient's immunological status. Int J Cardiol. 2015;189:115–23.

    Article  Google Scholar 

  6. Hofmann U, Beyersdorf N, Weirather J, Podolskaya A, Bauersachs J, Ertl G, et al. Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation. 2012;125(13):1652–63.

    Article  CAS  Google Scholar 

  7. Yan X, Shichita T, Katsumata Y, Matsuhashi T, Ito H, Ito K, et al. Deleterious effect of the IL-23/IL-17A axis and gammadeltaT cells on left ventricular remodeling after myocardial infarction. J Am Heart Assoc. 2012;1(5):e004408.

    Article  Google Scholar 

  8. Kelly GS. Rhodiola rosea: a possible plant adaptogen. Altern Med Rev. 2001;6(3):293–302.

    CAS  PubMed  Google Scholar 

  9. Lee SY, Li MH, Shi LS, Chu H, Ho CW, Chang TC. Rhodiola crenulata extract alleviates hypoxic pulmonary edema in rats. Evid Based Complement Alternat Med. 2013;2013:718–39.

    Google Scholar 

  10. Yang YN, Liu ZZ, Feng ZM, Jiang JS, Zhang PC. Lignans from the root of Rhodiola crenulata. J Agric Food Chem. 2012;60(4):964–72.

    Article  CAS  Google Scholar 

  11. Han X, Zhang T, Wei Y, Cao X, Ito Y. Separation of salidroside from Rhodiola crenulata by high-speed counter-current chromatography. J Chromatogr A. 2002;971(1–2):237–41.

    Article  CAS  Google Scholar 

  12. Wang XL, Wang X, Xiong LL, Zhu Y, Chen HL, Chen JX, et al. Salidroside improves doxorubicin-induced cardiac dysfunction by suppression of excessive oxidative stress and cardiomyocyte apoptosis. J Cardiovasc Pharmacol. 2013;62(6):512–23.

    Article  CAS  Google Scholar 

  13. Liu SH, Hsiao YW, Chong E, Singhal R, Fong MC, Tsai YN, et al. Rhodiola inhibits atrial arrhythmogenesis in a heart failure model. J Cardiovasc Electrophysiol. 2016;27(9):1093–101.

    Article  Google Scholar 

  14. Chang SL, Chen YC, Hsu CP, Kao YH, Lin YK, Lai YJ, et al. Heat shock protein inducer modifies arrhythmogenic substrate and inhibits atrial fibrillation in the failing heart. Int J Cardiol. 2013;168(4):4019–26.

    Article  Google Scholar 

  15. Chang SL, Chen YC, Hsu CP, Kao YH, Lin YK, Lin YJ, et al. Electrophysiological characteristics of complex fractionated electrograms and high frequency activity in atrial fibrillation. Int J Cardiol. 2013;168(3):2289–99.

    Article  Google Scholar 

  16. Chang SL, Hsiao YW, Tsai YN, Lin SF, Liu SH, Lin YJ, et al. Interleukin-17 enhances cardiac ventricular remodeling via activating MAPK pathway in ischemic heart failure. J Mol Cell Cardiol. 2018;122:69–79.

    Article  CAS  Google Scholar 

  17. Wang J, Rong X, Li W, Yang Y, Yamahara J, Li Y. Rhodiola crenulata root ameliorates derangements of glucose and lipid metabolism in a rat model of the metabolic syndrome and type 2 diabetes. J Ethnopharmacol. 2012;142(3):782–8.

    Article  CAS  Google Scholar 

  18. Yamada S, Fong MC, Hsiao YW, Chang SL, Tsai YN, Lo LW, et al. Impact of renal denervation on atrial arrhythmogenic substrate in ischemic model of heart failure. J Am Heart Assoc. 2018;7:2.

    Article  Google Scholar 

  19. Zhou SF, Yuan J, Liao MY, Xia N, Tang TT, Li JJ, et al. IL-17A promotes ventricular remodeling after myocardial infarction. J Mol Med. 2014;92(10):1105–16.

    Article  CAS  Google Scholar 

  20. Ikeda Y, Inomata T, Fujita T, Iida Y, Nabeta T, Ishii S, et al. Cardiac fibrosis detected by magnetic resonance imaging on predicting time course diversity of left ventricular reverse remodeling in patients with idiopathic dilated cardiomyopathy. Heart Vessel. 2016;31(11):1817–25.

    Article  Google Scholar 

  21. Ishaque S, Shamseer L, Bukutu C, Vohra S. Rhodiola rosea for physical and mental fatigue: a systematic review. BMC Complement Altern Med. 2012;12:70.

    Article  Google Scholar 

  22. Wu T, Zhou H, Jin Z, Bi S, Yang X, Yi D, et al. Cardioprotection of salidroside from ischemia/reperfusion injury by increasing N-acetylglucosamine linkage to cellular proteins. Eur J Pharmacol. 2009;613(1–3):93–9.

    Article  CAS  Google Scholar 

  23. Zhang J, Liu A, Hou R, Zhang J, Jia X, Jiang W, et al. Salidroside protects cardiomyocyte against hypoxia-induced death: a HIF-1alpha-activated and VEGF-mediated pathway. Eur J Pharmacol. 2009;607(1–3):6–14.

    Article  CAS  Google Scholar 

  24. Lee WJ, Chung HH, Cheng YZ, Lin HJ, Cheng JT. Rhodiola-water extract induces beta-endorphin secretion to lower blood pressure in spontaneously hypertensive rats. Phytother Res. 2013;27(10):1543–7.

    PubMed  Google Scholar 

  25. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002;53(1):31–47.

    Article  CAS  Google Scholar 

  26. Valente AJ, Yoshida T, Gardner JD, Somanna N, Delafontaine P, Chandrasekar B. Interleukin-17A stimulates cardiac fibroblast proliferation and migration via negative regulation of the dual-specificity phosphatase MKP-1/DUSP-1. Cell Signal. 2012;24(2):560–8.

    Article  CAS  Google Scholar 

  27. Monnerat G, Alarcon ML, Vasconcellos LR, Hochman-Mendez C, Brasil G, Bassani RA, et al. Macrophage-dependent IL-1beta production induces cardiac arrhythmias in diabetic mice. Nat Commun. 2016;7:13344.

    Article  CAS  Google Scholar 

  28. Toldo S, Marchetti C, Mauro AG, Chojnacki J, Mezzaroma E, Carbone S, et al. Inhibition of the NLRP3 inflammasome limits the inflammatory injury following myocardial ischemia-reperfusion in the mouse. Int J Cardiol. 2016;209:215–20.

    Article  Google Scholar 

  29. Yao C, Veleva T, Scott L Jr, Cao S, Li L, Chen G, et al. Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation. 2018;138(20):2227–42.

    Article  CAS  Google Scholar 

  30. Mesquita TRR, Zhang R, de Couto G, Valle J, Sanchez L, Rogers RG, et al. Mechanisms of atrial fibrillation in aged rats with heart failure with preserved ejection fraction. Heart Rhythm. 2020;17(6):1025–33.

    Article  Google Scholar 

  31. Bellahcene M, Jacquet S, Cao XB, Tanno M, Haworth RS, Layland J, et al. Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor. J Am Coll Cardiol. 2006;48(3):545–55.

    Article  CAS  Google Scholar 

  32. Xiang T, Long H, He L, Han X, Lin K, Liang Z, et al. Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer. Oncogene. 2015;34(2):165–76.

    Article  CAS  Google Scholar 

  33. Cheng YZ, Chen LJ, Lee WJ, Chen MF, Jung Lin H, Cheng JT. Increase of myocardial performance by Rhodiola-ethanol extract in diabetic rats. J Ethnopharmacol. 2012;144(2):234–9.

    Article  Google Scholar 

  34. Sun MY, Ma DS, Zhao S, Wang L, Ma CY, Bai Y. Salidroside mitigates hypoxia/reoxygenation injury by alleviating endoplasmic reticulum stress-induced apoptosis in H9c2 cardiomyocytes. Mol Med Rep. 2018;18(4):3760–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Woron J, Siwek M. Unwanted effects of psychotropic drug interactions with medicinal products and diet supplements containing plant extracts. Psychiatr Pol. 2018;52(6):983–96.

    Article  Google Scholar 

  36. Maslov LN, Lishmanov YB, Arbuzov AG, Krylatov AV, Budankova EV, Konkovskaya YN, et al. Antiarrhythmic activity of phytoadaptogens in short-term ischemia-reperfusion of the heart and postinfarction cardiosclerosis. Bull Exp Biol Med. 2009;147(3):331–4.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Taipei Veterans General Hospital grant [V108C-055, V107C-041, V106C-056, VGHUST107-G1-7-1, MOST 106-2314-B-010-035-MY3, MOST 105-2314-B-075-036, MOST104-2314-B-075-0, MOST104-2314-B-075-024-MY3] and SZU-YUAN Research Foundation of Internal Medicine.

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Author notes

  1. Ya-Wen Hsiao and Yung-Nan Tsai contributed equally to this work.

Authors and Affiliations

  1. Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, 201 Sec- 2, Shih-Pai Road, Taipei, Taiwan

    Ya-Wen Hsiao, Yu-Ting Huang, Yenn-Jiang Lin, Li-Wei Lo, Yu-Feng Hu, Fa-Po Chung, Shih-Lin Chang & Shih-Ann Chen

  2. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Yung-Nan Tsai

  3. Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan

    Shuen-Hsin Liu

  4. Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan

    Yenn-Jiang Lin, Li-Wei Lo, Yu-Feng Hu, Fa-Po Chung, Shih-Lin Chang & Shih-Ann Chen

  5. Institute of Biomedical Engineering, National Chiao Tung University, Hsinchu, Taiwan

    Shien-Fong Lin

  6. Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa, Japan

    Satoshi Higa

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  1. Ya-Wen Hsiao
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Contributions

Hsiao YW and Chang SL designed the project and wrote the manuscript. Hsiao YW, Tsai YN, and Huang YT performed the experiments and analyzed the data. All authors read and approved the final manuscript.

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Correspondence to Shih-Lin Chang.

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Hsiao, YW., Tsai, YN., Huang, YT. et al. Rhodiola crenulata reduces ventricular arrhythmia through mitigating the activation of IL-17 and inhibiting the MAPK signaling pathway. Cardiovasc Drugs Ther 35, 889–900 (2021). https://doi.org/10.1007/s10557-020-07072-z

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