Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside Rg1 attenuates mechanical stress-induced cardiac injury via calcium sensing receptor-related pathway

  • Lu, Mei-Li (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Wang, Jing (The First Affiliated Hospital of Jinzhou Medical University) ;
  • Sun, Yang (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Li, Cong (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Sun, Tai-Ran (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University) ;
  • Hou, Xu-Wei (The Department of Human Anatomy of Jinzhou Medical University) ;
  • Wang, Hong-Xin (The Key Laboratory of Cardiovascular and Cerebrovascular Drug Research of Liaoning Province, Jinzhou Medical University)
  • Received : 2020.01.02
  • Accepted : 2021.03.21
  • Published : 2021.11.15
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Abstract

Background: Ginsenoside Rg1 (Rg1) has been well documented to be effective against various cardiovascular disease. The aim of this study is to evaluate the effect of Rg1 on mechanical stress-induced cardiac injury and its possible mechanism with a focus on the calcium sensing receptor (CaSR) signaling pathway. Methods: Mechanical stress was implemented on rats through abdominal aortic constriction (AAC) procedure and on cardiomyocytes and cardiac fibroblasts by mechanical stretching with Bioflex Collagen I plates. The effects of Rg1 on cell hypertrophy, fibrosis, cardiac function, [Ca2+]i, and the expression of CaSR and calcineurin (CaN) were assayed both on rat and cellular level. Results: Rg1 alleviated cardiac hypertrophy and fibrosis, and improved cardiac decompensation induced by AAC in rat myocardial tissue and cultured cardiomyocytes and cardiac fibroblasts. Importantly, Rg1 treatment inhibited CaSR expression and increase of [Ca2+]i, which similar to the CaSR inhibitor NPS2143. In addition, Rg1 treatment inhibited CaN and TGF-b1 pathways activation. Mechanistic analysis showed that the CaSR agonist GdCl3 could not further increase the [Ca2+]i and CaN pathway related protein expression induced by mechanical stretching in cultured cardiomyocytes. CsA, an inhibitor of CaN, inhibited cardiac hypertrophy, cardiac fibrosis, [Ca2+]i and CaN signaling but had no effect on CaSR expression. Conclusion: The activation of CaN pathway and the increase of [Ca2+]i mediated by CaSR are involved in cardiac hypertrophy and fibrosis, that may be the target of cardioprotection of Rg1 against myocardial injury.

Keywords

Acknowledgement

The present study was supported by Nation Science Foundation Project (81973553), Guide Planned Project of Liaoning Province (No. 2019-ZD-0617 and JYTJCZR2020077).

References

  1. Li X, Chu G, Zhu F, Zheng Z, Wang X, Zhang G, Wang F. Epoxyeicosatrienoic acid prevents maladaptiveremodeling in pressure overload by targeting calcineurin/NFAT and Smad-7. Exp Cell Res 2019:111716. https://doi.org/10.1016/j.yexcr.2019.111716
  2. Zheng RH, Bai XJ, Zhang WW, Wang J, Bai F, Yan CP, James EA, Bose HS, Wang NP, Zhao ZQ. Liraglutide attenuates cardiac remodeling and improves heart function after abdominal aortic constriction through blocking angiotensin II type 1 receptor in rats. Drug Des Devel Ther 2019;13:2745-57. https://doi.org/10.2147/DDDT.S213910
  3. Jiang WY, Huo JY, Chen C, Chen R, Ge TT, Chang Q, Hu JW, Geng J, Jiang ZX, Shan QJ. Renal denervation ameliorates post-infarction cardiac remodeling in rats through dual regulation of oxidative stress in the heart and brain. Biomed Pharmacother 2019;118:109243. https://doi.org/10.1016/j.biopha.2019.109243
  4. Glasenapp A, Derlin K, Wang Y, Bankstahl M, Meier M, Wollert KC, Bengel FM, Thackeray JT. Multimodality imaging of inflammation and ventricular remodeling in pressure overload heart failure. J Nucl Med 2019.
  5. Sun YH, Liu MN, Li H, Shi S, Zhao YJ, Wang R, Xu CQ. Calcium-sensing receptor induces rat neonatal ventricular cardiomyocyte apoptosis. Biochem Biophys Res Commun 2006;350:942-8. https://doi.org/10.1016/j.bbrc.2006.09.142
  6. Tfelt-Hansen J, Hansen JL, Smajilovic S, Terwilliger EF, Haunso S, Sheikh SP. Calcium receptor is functionally expressed in rat neonatal ventricular cardiomyocytes. Am J Physiol Heart Circ Physiol 2006;290:H1165-71. https://doi.org/10.1152/ajpheart.00821.2005
  7. Chi J, Wang L, Zhang X, Fu Y, Liu Y, Chen W, Liu W, Shi Z, Yin X. Activation of calcium-sensing receptor-mediated autophagy in angiotensinII-induced cardiac fibrosis in vitro. Biochem Biophys Res Commun 2018;497:571-6. https://doi.org/10.1016/j.bbrc.2018.02.098
  8. Spurr NK. Genetics of calcium-sensing-regulation of calcium levels in the body. Curr Opin Pharmacol 2003;3:291-4. https://doi.org/10.1016/S1471-4892(03)00034-1
  9. Jiang CM, Han LP, Li HZ, Qu YB, Zhang ZR, Wang R, Xu CQ, Li WM. Calcium-sensing receptors induce apoptosis in cultured neonatal rat ventricular cardiomyocytes during simulated ischemia/reperfusion. Cell Biol Int 2008;32:792-800. https://doi.org/10.1016/j.cellbi.2008.03.009
  10. Lu F, Tian Z, Zhang W, Zhao Y, Bai S, Ren H, Chen H, Yu X, Wang J, Wang L, et al. Calcium-sensing receptors induce apoptosis in rat cardiomyocytes via the endo(sarco)plasmic reticulum pathway during hypoxia/reoxygenation. Basic Clin Pharmacol Toxicol 2010;106:396-405. https://doi.org/10.1111/j.1742-7843.2009.00502.x
  11. Zheng H, Liu J, Liu C, Lu F, Zhao Y, Jin Z, Ren H, Leng X, Jia J, Hu G, et al. Calcium-sensing receptor activating phosphorylation of PKCdelta translocation on mitochondria to induce cardiomyocyte apoptosis during ischemia/reperfusion. Mol Cell Biochem 2011;358:335-43. https://doi.org/10.1007/s11010-011-0984-1
  12. Lu M, Leng B, He X, Zhang Z, Wang H, Tang F. Calcium sensing receptor-related pathway contributes to cardiac injury and the mechanism of astragaloside IV on cardioprotection. Front Pharmacol 2018;9:1163. https://doi.org/10.3389/fphar.2018.01163
  13. Lu FH, Fu SB, Leng X, Zhang X, Dong S, Zhao YJ, Ren H, Li H, Zhong X, Xu CQ, et al. Role of the calcium-sensing receptor in cardiomyocyte apoptosis via the sarcoplasmic reticulum and mitochondrial death pathway in cardiac hypertrophy and heart failure. Cell Physiol Biochem 2013;31:728-43. https://doi.org/10.1159/000350091
  14. Hong S, Zhang X, Zhang X, Liu W, Fu Y, Liu Y, Shi Z, Chi J, Zhao M, Yin X. Role of the calcium sensing receptor in cardiomyocyte apoptosis via mitochondrial dynamics in compensatory hypertrophied myocardium of spontaneously hypertensive rat. Biochem Biophys Res Commun 2017;487:728-33. https://doi.org/10.1016/j.bbrc.2017.04.126
  15. Wang J, Wang Y, Zhang W, Zhao X, Chen X, Xiao W, Zhang L, Chen Y, Zhu W. Phenylephrine promotes cardiac fibroblast proliferation through calcineurin-NFAT pathway. Front Biosci (Landmark Ed) 2016;21:502-13. https://doi.org/10.2741/4405
  16. Tsai CY, Kuo WW, Shibu MA, Lin YM, Liu CN, Chen YH, Day CH, Shen CY, Viswanadha VP, Huang CY. E2/ER beta inhibit ISO-induced cardiac cellular hypertrophy by suppressing Ca2+-calcineurin signaling. PLoS One 2017;12:e0184153. https://doi.org/10.1371/journal.pone.0184153
  17. Liu CJ, Cheng YC, Lee KW, Hsu HH, Chu CH, Tsai FJ, Tsai CH, Chu CY, Liu JY, Kuo WW, et al. Lipopolysaccharide induces cellular hypertrophy through calcineurin/NFAT-3 signaling pathway in H9c2 myocardiac cells. Mol Cell Biochem 2008;313:167-78. https://doi.org/10.1007/s11010-008-9754-0
  18. Saygili E, Rana OR, Meyer C, Gemein C, Andrzejewski MG, Ludwig A, Weber C, Schotten U, Kruttgen A, Weis J, et al. The angiotensin-calcineurin-NFAT pathway mediates stretch-induced up-regulation of matrix metalloproteinases-2/-9 in atrial myocytes. Basic Res Cardiol 2009;104:435-48. https://doi.org/10.1007/s00395-008-0772-6
  19. Finsen AV, Lunde IG, Sjaastad I, Ostli EK, Lyngra M, Jarstadmarken HO, Hasic A, Nygard S, Wilcox-Adelman SA, Goetinck PF, et al. Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway. PLoS One 2011;6:e28302. https://doi.org/10.1371/journal.pone.0028302
  20. Zhou N, Li L, Wu J, Gong H, Niu Y, Sun A, Ge J, Zou Y. Mechanical stress-evoked but angiotensin II-independent activation of angiotensin II type 1 receptor induces cardiac hypertrophy through calcineurin pathway. Biochem Biophys Res Commun 2010;397:263-9. https://doi.org/10.1016/j.bbrc.2010.05.097
  21. Fan X, Zhang C, Niu S, Fan B, Gu D, Jiang K, Li R, Li S. Ginsenoside Rg1 attenuates hepatic insulin resistance induced by high-fat and high-sugar by inhibiting inflammation. Eur J Pharmacol 2019;854:247-55. https://doi.org/10.1016/j.ejphar.2019.04.027
  22. Xu Y, Yang C, Zhang S, Li J, Xiao Q, Huang W. Ginsenoside Rg1 protects against non-alcoholic fatty liver disease by ameliorating lipid peroxidation, endoplasmic reticulum stress, and inflammasome activation. Biol Pharm Bull 2018;41:1638-44. https://doi.org/10.1248/bpb.b18-00132
  23. Xu ZM, Li CB, Liu QL, Li P, Yang H. Ginsenoside Rg1 prevents doxorubicin-induced cardiotoxicity through the inhibition of autophagy and endoplasmic reticulum stress in mice. Int J Mol Sci 2018;19.
  24. Qin Q, Lin N, Huang H, Zhang X, Cao X, Wang Y, Li P. Ginsenoside Rg1 ameliorates cardiac oxidative stress and inflammation in streptozotocin-induced diabetic rats. Diabetes Metab Syndr Obes 2019;12:1091-103. https://doi.org/10.2147/DMSO.S208989
  25. Li L, Pan CS, Yan L, Cui YC, Liu YY, Mu HN, He K, Hu BH, Chang X, Sun K, et al. Ginsenoside Rg1 ameliorates rat myocardial ischemia-reperfusion injury by modulating energy metabolism pathways. Front Physiol 2018;9:78. https://doi.org/10.3389/fphys.2018.00078
  26. Tang F, Lu M, Yu L, Wang Q, Mei M, Xu C, Han R, Hu J, Wang H, Zhang Y. Inhibition of TNF-alpha-mediated NF-kappaB activation by ginsenoside Rg1 contributes the attenuation of cardiac hypertrophy induced by abdominal aorta coarctation. J Cardiovasc Pharmacol 2016;68:257-64. https://doi.org/10.1097/FJC.0000000000000410
  27. Xu TZ, Shen XY, Sun LL, Chen YL, Zhang BQ, Huang DK, Li WZ. Ginsenoside Rg1 protects against H2O2induced neuronal damage due to inhibition of the NLRP1 inflammasome signalling pathway in hippocampal neurons in vitro. Int J Mol Med 2019;43:717-26.
  28. Park S, Ahn IS, Kwon DY, Ko BS, Jun WK. Ginsenosides Rb1 and Rg1 suppress triglyceride accumulation in 3T3-L1 adipocytes and enhance beta-cell insulin secretion and viability in Min6 cells via PKA-dependent pathways. Biosci Biotechnol Biochem 2008;72:2815-23. https://doi.org/10.1271/bbb.80205
  29. Huang Y, Zou Y, Lin L, Zheng R. Ginsenoside Rg1 activates dendritic cells and acts as a vaccine adjuvant inducing protective cellular responses against lymphomas. DNA Cell Biol 2017;36:1168-77. https://doi.org/10.1089/dna.2017.3923
  30. Xu Z, Li C, Liu Q, Yang H, Li P. Ginsenoside Rg1 protects H9c2 cells against nutritional stress-induced injury via aldolase/AMPK/PINK1 signalling. J Cell Biochem 2019;120:18388-97. https://doi.org/10.1002/jcb.29150
  31. Zhang YJ, Zhang XL, Li MH, Iqbal J, Bourantas CV, Li JJ, Su XY, Muramatsu T, Tian NL, Chen SL. The ginsenoside Rg1 prevents transverse aortic constriction-induced left ventricular hypertrophy and cardiac dysfunction by inhibiting fibrosis and enhancing angiogenesis. J Cardiovasc Pharmacol 2013;62:50-7. https://doi.org/10.1097/fjc.0b013e31828f8d45
  32. Tornatore TF, Dalla Costa AP, Clemente CF, Judice C, Rocco SA, Calegari VC, Cardoso L, Cardoso AC, Goncalves Jr A, Franchini KG. A role for focal adhesion kinase in cardiac mitochondrial biogenesis induced by mechanical stress. Am J Physiol Heart Circ Physiol 2011;300:H902-12. https://doi.org/10.1152/ajpheart.00319.2010
  33. Wang LN, Wang C, Lin Y, Xi YH, Zhang WH, Zhao YJ, Li HZ, Tian Y, Lv YJ, Yang BF, et al. Involvement of calcium-sensing receptor in cardiac hypertrophy-induced by angiotensinII through calcineurin pathway in cultured neonatal rat cardiomyocytes. Biochem Biophys Res Commun 2008;369:584-9. https://doi.org/10.1016/j.bbrc.2008.02.053
  34. Liu L, Wang C, Sun D, Jiang S, Li H, Zhang W, Zhao Y, Xi Y, Shi S, Lu F, et al. Calhex(2)(3)(1) ameliorates cardiac hypertrophy by inhibiting cellular autophagy in vivo and in vitro. Cell Physiol Biochem 2015;36:1597-612. https://doi.org/10.1159/000430322
  35. Calaghan SC, White E. The role of calcium in the response of cardiac muscle to stretch. Prog Biophys Mol Biol 1999;71:59-90. https://doi.org/10.1016/S0079-6107(98)00037-6
  36. Molostvov G, Hiemstra TF, Fletcher S, Bland R, Zehnder D. Arterial expression of the calcium-sensing receptor is maintained by physiological pulsation and protects against calcification. PLoS One 2015;10:e0138833. https://doi.org/10.1371/journal.pone.0138833
  37. Ruwhof C, van Wamel JT, Noordzij LA, Aydin S, Harper JC, van der Laarse A. Mechanical stress stimulates phospholipase C activity and intracellular calcium ion levels in neonatal rat cardiomyocytes. Cell Calcium 2001;29:73-83. https://doi.org/10.1054/ceca.2000.0158
  38. Kumar S, Wang G, Liu W, Ding W, Dong M, Zheng N, Ye H, Liu J. Hypoxiainduced mitogenic factor promotes cardiac hypertrophy via calcium-dependent and hypoxia-inducible factor-1alpha mechanisms. Hypertension 2018;72:331-42. https://doi.org/10.1161/HYPERTENSIONAHA.118.10845
  39. Wei WY, Zhang N, Li LL, Ma ZG, Xu M, Yuan YP, Deng W, Tang QZ. Pioglitazone alleviates cardiac fibrosis and inhibits endothelial to mesenchymal transition induced by pressure overload. Cell Physiol Biochem 2018;45:26-36. https://doi.org/10.1159/000486220
  40. Chen HH, Zhao P, Zhao WX, Tian J, Guo W, Xu M, Zhang C, Lu R. Stachydrine ameliorates pressure overload-induced diastolic heart failure by suppressing myocardial fibrosis. Am J Transl Res 2017;9:4250-60.
  41. Yuan H, Fan Y, Wang Y, Gao T, Shao Y, Zhao B, Li H, Xu C, Wei C. Calcium-sensing receptor promotes high glucoseinduced myocardial fibrosis via upregulation of the TGFbeta1/Smads pathway in cardiac fibroblasts. Mol Med Rep 2019;20:1093-102.