Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Ginsenoside Rg3 ameliorates myocardial glucose metabolism and insulin resistance via activating the AMPK signaling pathway

  • Ni, Jingyu (National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine) ;
  • Liu, Zhihao (National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine) ;
  • Jiang, Miaomiao (Tianjin State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine) ;
  • Li, Lan (National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine) ;
  • Deng, Jie (National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine) ;
  • Wang, Xiaodan (National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine) ;
  • Su, Jing (Tianjin State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine) ;
  • Zhu, Yan (Tianjin State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine) ;
  • He, Feng (Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization, Huanggang Normal University) ;
  • Mao, Jingyuan (National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine) ;
  • Gao, Xiumei (Tianjin State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine) ;
  • Fan, Guanwei (National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine)
  • Received : 2020.11.13
  • Accepted : 2021.06.01
  • Published : 2022.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Ginsenoside Rg3 is one of the main active ingredients in ginseng. Here, we aimed to confirm its protective effect on the heart function in transverse aortic coarctation (TAC)-induced heart failure mice and explore the potential molecular mechanisms involved. Methods: The effects of ginsenoside Rg3 on heart and mitochondrial function were investigated by treating TAC-induced heart failure in mice. The mechanism of ginsenoside Rg3 for improving heart and mitochondrial function in mice with heart failure was predicted through integrative analysis of the proteome and plasma metabolome. Glucose uptake and myocardial insulin sensitivity were evaluated using micro-positron emission tomography. The effect of ginsenoside Rg3 on myocardial insulin sensitivity was clarified by combining in vivo animal experiments and in vitro cell experiments. Results: Treatment of TAC-induced mouse models with ginsenoside Rg3 significantly improved heart function and protected mitochondrial structure and function. Fusion of metabolomics, proteomics, and targeted metabolomics data showed that Rg3 regulated the glycolysis process, and Rg3 not only regulated glucose uptake but also improve myocardial insulin resistance. The molecular mechanism of ginsenoside Rg3 regulation of glucose metabolism was determined by exploring the interaction pathways of AMPK, insulin resistance, and glucose metabolism. The effect of ginsenoside Rg3 on the promotion of glucose uptake in IR-H9c2 cells by AMPK activation was dependent on the insulin signaling pathway. Conclusions: Ginsenoside Rg3 modulates glucose metabolism and significantly ameliorates insulin resistance through activation of the AMPK pathway.

Keywords

Acknowledgement

This work was supported by grants from the National Key Subject of Drug Innovation (No.2019ZX09201005-007), Tianjin Outstanding Youth Science Foundation (No.17JCJQJC46200), the National Natural Science Foundation of China (No.81774050), the Natural Science Foundation of Tianjin (17JCYBJC29000).

References

  1. van Bilsen M, Smeets PJ, Gilde AJ, van der Vusse GJ. Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res 2004;61:218-26. https://doi.org/10.1016/j.cardiores.2003.11.014
  2. Ritchie RH, Delbridge LM. Cardiac hypertrophy, substrate utilization and metabolic remodelling: cause or effect? Clin Exp Pharmacol Physiol 2006;33:159-66. https://doi.org/10.1111/j.1440-1681.2006.04342.x
  3. Bertero E, Maack C. Metabolic remodelling in heart failure. Nat Rev Cardiol 2018;15:457-70. https://doi.org/10.1038/s41569-018-0044-6
  4. Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 2013;113:709-24. https://doi.org/10.1161/CIRCRESAHA.113.300376
  5. Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol 2014;64: 1388-400. https://doi.org/10.1016/j.jacc.2014.04.083
  6. Lopaschuk GD, Ussher JR. Evolving concepts of myocardial energy metabolism: more than just fats and carbohydrates. Circ Res 2016;119:1173-6. https://doi.org/10.1161/CIRCRESAHA.116.310078
  7. Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2012;32: 2052-9. https://doi.org/10.1161/ATVBAHA.111.241919
  8. Heck PM, Dutka DP. Insulin resistance and heart failure. Curr Heart Fail Rep 2009;6:89-94. https://doi.org/10.1007/s11897-009-0014-8
  9. Guo CA, Guo S. Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure. J Endocrinol 2017;233:R131-43. https://doi.org/10.1530/JOE-16-0679
  10. Lopaschuk GD. Fatty acid oxidation and its relation with insulin resistance and associated disorders. Ann Nutr Metab 2016;68(Supplement 3):15-20. https://doi.org/10.1159/000448357
  11. Patel TP, Rawal K, Bagchi AK, Akolkar G, Bernardes N, Dias DDS, Gupta S, Singal PK. Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes. Heart Fail Rev 2016;21:11-23. https://doi.org/10.1007/s10741-015-9515-6
  12. Ingelsson E, Sundstrom J, Arnlov J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure. JAMA 2005;294:334-41. https://doi.org/10.1001/jama.294.3.334
  13. Vardeny O, Gupta DK, Claggett B, Burke S, Shah A, Loehr L, Rasmussen-Torvik L, Selvin E, Chang PP, Aguilar D, et al. Insulin resistance and incident heart failure the ARIC study (Atherosclerosis Risk in Communities). JACC Heart Fail 2013;1:531-6. https://doi.org/10.1016/j.jchf.2013.07.006
  14. Greene SJ, Fonarow GC. Insulin resistance in heart failure: widening the divide between reduced and preserved ejection fraction? Eur J Heart Fail 2015;17:991-3. https://doi.org/10.1002/ejhf.337
  15. Fu F, Zhao K, Li J, Xu J, Zhang Y, Liu C, Yang W, Gao C, Li J, Zhang H, et al. Direct Evidence that myocardial insulin resistance following myocardial ischemia Contributes to Post-Ischemic Heart Failure. Sci. Rep.:17927. Sci Rep 2015;5:17927. https://doi.org/10.1038/srep17927
  16. Novo G, Manno G, Russo R, Buccheri D, Dell'Oglio S, Morreale P, Evola G, Vitale G, Novo S. Impact of insulin resistance on cardiac and vascular function. Int J Cardiol 2016;221:1095-9. https://doi.org/10.1016/j.ijcard.2016.07.087
  17. Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C, Zuniga FA. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc Diabetol 2018;17:122. https://doi.org/10.1186/s12933-018-0762-4
  18. Salt IP, Hardie DG. AMP-activated protein kinase: an ubiquitous signaling pathway with key roles in the cardiovascular system. Circ Res 2017;120:1825-41. https://doi.org/10.1161/CIRCRESAHA.117.309633
  19. Qi D, Young LH. AMPK: energy sensor and survival mechanism in the ischemic heart. Trends Endocrinol Metab 2015;26:422-9. https://doi.org/10.1016/j.tem.2015.05.010
  20. Smith BK, Steinberg GR. AMP-activated protein kinase, fatty acid metabolism, and insulin sensitivity. Curr Opin Clin Nutr Metab Care 2017;20:248-53. https://doi.org/10.1097/MCO.0000000000000380
  21. Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med 2016;48:e224. https://doi.org/10.1038/emm.2016.16
  22. Cheng L, Sun X, Hu C, Jin R, Sun B, Shi Y, Cui W, Zhang Y. In vivo early intervention and the therapeutic effects of 20(s)-ginsenoside rg3 on hypertrophic scar formation. PLOS ONE 2014;9:e113640. https://doi.org/10.1371/journal.pone.0113640
  23. Cheng L, Sun X, Li B, Hu C, Yang H, Zhang Y, Cui W. Electrospun ginsenoside Rg3/poly(lactic-co-glycolic acid) fibers coated with hyaluronic acid for repairing and inhibiting hypertrophic scars. J Mater Chem B 2013;1:4428-37. https://doi.org/10.1039/c3tb20441c
  24. Smith I, Williamson EM, Putnam S, Farrimond J, Whalley BJ. Effects and mechanisms of ginseng and ginsenosides on cognition. Nutr Rev 2014;72:319-33. https://doi.org/10.1111/nure.12099
  25. Li L, Ni J, Li M, Chen J, Han L, Zhu Y, Kong D, Mao J, Wang Y, Zhang B, et al. Ginsenoside Rg3 micelles mitigate doxorubicin-induced cardiotoxicity and enhance its anticancer efficacy. Drug Deliv 2017;24:1617-30. https://doi.org/10.1080/10717544.2017.1391893
  26. Li L, Wang Y, Guo R, Li S, Ni J, Gao S, Gao X, Mao J, Zhu Y, Wu P, et al. Ginsenoside Rg3-loaded, reactive oxygen species-responsive polymeric nanoparticles for alleviating myocardial ischemia-reperfusion injury. J Control Release 2020;317:259-72. https://doi.org/10.1016/j.jconrel.2019.11.032
  27. Tavakoli R, Nemska S, Jamshidi P, Gassmann M, Frossard N. Technique of minimally invasive transverse aortic constriction in mice for induction of left ventricular hypertrophy. J Vis Exp 2017;127:56231.
  28. deAlmeida AC, van Oort RJ, Wehrens XH. Transverse aortic constriction in mice. J Vis Exp 2010;38:1729.
  29. Ni J, Zhao Y, Su J, Liu Z, Fang S, Li L, Deng J, Fan G. Toddalolactone protects lipopolysaccharide-induced sepsis and attenuates lipopolysaccharide-induced inflammatory response by modulating HMGB1-NF-κB translocation. Front Pharmacol 2020 Feb 21;11:109. https://doi.org/10.3389/fphar.2020.00109
  30. Kirshenbaum LA, Singal PK. Antioxidant changes in heart hypertrophy: significance during hypoxia-reoxygenation injury. Can J Physiol Pharmacol 1992;70:1330-5. https://doi.org/10.1139/y92-186
  31. Chen JR, Wei J, Wang LY, Zhu Y, Li L, Olunga MA, Gao XM, Fan GW. Cardioprotection against ischemia/reperfusion injury by QiShenYiQi Pill® via ameliorate of multiple mitochondrial dysfunctions. Drug Des Dev Ther 2015;9:3051-66.
  32. Boutagy NE, Rogers GW, Pyne ES, Ali MM, Hulver MW, Frisard MI. Using isolated mitochondria from minimal quantities of mouse skeletal muscle for high throughput microplate respiratory measurements. J Vis Exp 2015;105:e53216.
  33. Dong Z, Zhao P, Xu M, Zhang C, Guo W, Chen H, Tian J, Wei H, Lu R, Cao T. Astragaloside IV alleviates heart failure via activating PPARa to switch glycolysis to fatty acid b-oxidation. Sci. Rep.:2691. Sci Rep 2017;7:2691. https://doi.org/10.1038/s41598-017-02360-5
  34. Jiang M, Ni J, Cao Y, Xing X, Wu Q, Fan G. Astragaloside IV attenuates myocardial ischemia-reperfusion injury from oxidative stress by regulating succinate, lysophospholipid metabolism, and ROS Scavenging System. Oxid Med Cell Longev 2019 Jun 24;2019:9137654.
  35. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, Kogadeeva M, Picotti P, Meissner F, Mann M, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016 Oct 20;167:829-842.e13. https://doi.org/10.1016/j.cell.2016.09.031
  36. Fillmore N, Levasseur JL, Fukushima A, Wagg CS, Wang W, Dyck JRB, et al. Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction. Mol Med 2018;24:3. https://doi.org/10.1186/s10020-018-0005-x
  37. Gibb AA, Hill BG. Metabolic coordination of physiological and pathological cardiac remodeling. Circ Res 2018;123:107-28. https://doi.org/10.1161/CIRCRESAHA.118.312017
  38. Shao D, Tian R. Glucose transporters in cardiac metabolism and hypertrophy. Compr Physiol 2015;6:331-51. https://doi.org/10.1002/cphy.c150016