DOI QR코드

DOI QR Code

Total ginsenosides suppress monocrotaline-induced pulmonary hypertension in rats: involvement of nitric oxide and mitogen-activated protein kinase pathways

  • Qin, Na (Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine) ;
  • Yang, Wei (Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine) ;
  • Feng, Dongxu (Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine) ;
  • Wang, Xinwen (Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine) ;
  • Qi, Muyao (Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine) ;
  • Du, Tianxin (Department of Pharmacy, Luoyang Orthopedic Hospital, Orthopedics Hospital of Henan Province) ;
  • Sun, Hongzhi (Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an Jiaotong University School of Medicine) ;
  • Wu, Shufang (Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine)
  • Received : 2015.06.18
  • Accepted : 2015.09.30
  • Published : 2016.07.15

Abstract

Background: Ginsenosides have been shown to exert beneficial pharmacological effects on the central nervous, cardiovascular, and endocrine systems. We sought to determine whether total ginsenosides (TG) inhibit monocrotaline (MCT)-induced pulmonary hypertension and to elucidate the underlying mechanism. Methods: MCT-intoxicated rats were treated with gradient doses of TG, with or without $N^G$-nitro-$\small{L}$-arginine methyl ester. The levels of molecules involving the regulation of nitric oxide and mitogen-activated protein kinase pathways were determined. Results: TG ameliorated MCT-induced pulmonary hypertension in a dose-dependent manner, as assessed by the right ventricular systolic pressure, the right ventricular hypertrophy index, and pulmonary arterial remodeling. Furthermore, TG increased the levels of pulmonary nitric oxide, endothelial nitric oxide synthase, and cyclic guanosine monophosphate. Lastly, TG increased mitogen-activated protein kinase phosphatase-1 expression and promoted the dephosphorylation of extracellular signal-regulated protein kinases 1/2, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase 1/2. Conclusion: TG attenuates MCT-induced pulmonary hypertension, which may involve in part the regulation of nitric oxide and mitogen-activated protein kinase pathways.

Keywords

References

  1. Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med 2013;188:639-46. https://doi.org/10.1164/rccm.201304-0686PP
  2. Hampl V, Herget J. Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension. Physiol Rev 2000;80:1337-72. https://doi.org/10.1152/physrev.2000.80.4.1337
  3. Mathew R, Gloster ES, Sundararajan T, Thompson CI, Zeballos GA, Gewitz MH. Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension. J Appl Physiol (1985) 1997;82:1493-8. https://doi.org/10.1152/jappl.1997.82.5.1493
  4. Lu J, Shimpo H, Shimamoto A, Chong AJ, Hampton CR, Spring DJ, Yada M, Takao M, Onoda K, Yada I, et al. Specific inhibition of p38 mitogen-activated protein kinase with FR167653 attenuates vascular proliferation in monocrotaline-induced pulmonary hypertension in rats. J Thorac Cardiovasc Surg 2004;128:850-9. https://doi.org/10.1016/j.jtcvs.2004.03.003
  5. Yu MQ, Liu XS, Wu HX, Xiang M, Xu YJ. ERK1/2 promotes cigarette smoke-induced rat pulmonary artery smooth muscle cells proliferation and pulmonary vascular remodeling via up-regulating cycline1 expression. J Huazhong Univ Sci Technol Med Sci 2013;33:315-22. https://doi.org/10.1007/s11596-013-1117-8
  6. Fuzzati N, Gabetta B, Jayakar K, Pace R, Peterlongo F. Liquid chromatography-electrospray mass spectrometric identification of ginsenosides in Panax ginseng roots. J Chromatogr A 1999;854:69-79. https://doi.org/10.1016/S0021-9673(99)00463-X
  7. Li KK, Yang XB, Yang XW, Liu JX, Gong XJ. New triterpenoids from the stems and leaves of Panax ginseng. Fitoterapia 2012;83:1030-5. https://doi.org/10.1016/j.fitote.2012.05.013
  8. Kim JH. Cardiovascular Diseases and Panax ginseng: a review on molecular mechanisms and medical applications. J Ginseng Res 2012;36:16-26. https://doi.org/10.5142/jgr.2012.36.1.16
  9. Ahn HY, Hong SY, Kim JY, Kwon O. Panax ginseng extract rich in ginsenoside protopanaxatriol offers combinatorial effects in nitric oxide production via multiple signaling pathways. Springerplus 2013;2:96. https://doi.org/10.1186/2193-1801-2-96
  10. Yu XF, Deng J, Yang DL, Gao Y, Gong QH, Huang XN. Total ginsenosides suppress the neointimal hyperplasia of rat carotid artery induced by balloon injury. Vascul Pharmacol 2011;54:52-7. https://doi.org/10.1016/j.vph.2010.12.003
  11. Huang J, Li LS, Yang DL, Gong QH, Deng J, Huang XN. Inhibitory effect of ginsenoside Rg1 on vascular smooth muscle cell proliferation induced by PDGF-BB is involved in nitric oxide formation. Evid Based Complement Alternat Med 2012;2012, 314395.
  12. Qin N, Gong QH, Wei LW, Wu Q, Huang XN. Total ginsenosides inhibit the right ventricular hypertrophy induced by monocrotaline in rats. Biol Pharm Bull 2008;31:1530-5. https://doi.org/10.1248/bpb.31.1530
  13. Yi XQ, Li T, Wang JR, Wong VK, Luo P, Wong IY, Jiang ZH, Liu L, Zhou H. Total ginsenosides increase coronary perfusion flow in isolated rat hearts through activation of PI3K/Akt-eNOS signaling. Phytomedicine 2010;17:1006-15. https://doi.org/10.1016/j.phymed.2010.06.012
  14. Zheng GQ, Cheng W, Wang Y, Wang XM, Zhao SZ, Zhou Y, Liu SJ, Wang XT. Ginseng total saponins enhance neurogenesis after focal cerebral ischemia. J Ethnopharmacol 2011;133:724-8. https://doi.org/10.1016/j.jep.2010.01.064
  15. Barth PJ, Kimpel C, Roy S, Wagner U. An improved mathematical approach for the assessment of the medial thickness of pulmonary arteries. Pathol Res Pract 1993;189:567-76.
  16. Olschewski H, Ghofrani A, Wiedemann R, Rose F, Enke B, Gessler T, Voswinckel R, Kohstall M, Grimminger F, Seeger W. Pulmonary hypertension. Internist (Berl) 2002;43(1498):1501-9.
  17. Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. Rev Esp Cardiol 2005;58:523-66. https://doi.org/10.1157/13074846
  18. Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, Bogaard HJ. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 2012;302:L363-9. https://doi.org/10.1152/ajplung.00212.2011
  19. Mathew R, Yuan N, Rosenfeld L, Gewitz MH, Kumar A. Effects of monocrotaline on endothelial nitric oxide synthase expression and sulfhydryl levels in rat lungs. Heart Dis 2002;4:152-8. https://doi.org/10.1097/00132580-200205000-00004
  20. Tyler RC, Muramatsu M, Abman SH, Stelzner TJ, Rodman DM, Bloch KD, McMurtry IF. Variable expression of endothelial NO synthase in three forms of rat pulmonary hypertension. Am J Physiol 1999;276:L297-303.
  21. Resta TC, Gonzales RJ, Dail WG, Sanders TC, Walker BR. Selective upregulation of arterial endothelial nitric oxide synthase in pulmonary hypertension. Am J Physiol 1997;272:H806-13.
  22. Hong SY, Kim JY, Ahn HY, Shin JH, Kwon O. Panax ginseng extract rich in ginsenoside protopanaxatriol attenuates blood pressure elevation in spontaneously hypertensive rats by affecting the Akt-dependent phosphorylation of endothelial nitric oxide synthase. J Agric Food Chem 2012;60:3086-91. https://doi.org/10.1021/jf204447y
  23. Zeng Z, Li Y, Jiang Z, Wang C, Li B, Jiang W. The extracellular signal-regulated kinase is involved in the effects of sildenafil on pulmonary vascular remodeling. Cardiovasc Ther 2010;28:23-9. https://doi.org/10.1111/j.1755-5922.2009.00115.x
  24. Henriques-Coelho T, Oliveira SM, Moura RS, Roncon-Albuquerque Jr R, Neves AL, Santos M, Nogueira-Silva C, La Fuente Carvalho F, Brandao-Nogueira A, Correia-Pinto J, et al. Thymulin inhibits monocrotaline-induced pulmonary hypertension modulating interleukin-6 expression and suppressing p38 pathway. Endocrinology 2008;149:4367-73. https://doi.org/10.1210/en.2008-0018
  25. Bokemeyer D, Lindemann M, Kramer HJ. Regulation of mitogen-activated protein kinase phosphatase-1 in vascular smooth muscle cells. Hypertension 1998;32:661-7. https://doi.org/10.1161/01.HYP.32.4.661
  26. Bouallegue A, Daou GB, Srivastava AK. Nitric oxide attenuates endothelin-1-induced activation of ERK1/2, PKB, and Pyk2 in vascular smooth muscle cells by a cGMP-dependent pathway. Am J Physiol Heart Circ Physiol 2007;293:H2072-9. https://doi.org/10.1152/ajpheart.01097.2006
  27. Marathe N, Rangaswami H, Zhuang S, Boss GR, Pilz RB. Pro-survival effects of 17b-estradiol on osteocytes are mediated by nitric oxide/cGMP via differential actions of cGMP-dependent protein kinases I and II. J Biol Chem 2012;287:978-88. https://doi.org/10.1074/jbc.M111.294959

Cited by

  1. Ginseng Compatibility Environment Attenuates Toxicity and Keeps Efficacy in Cor Pulmonale Treated by Fuzi Beimu Incompatibility Through the Coordinated Crosstalk of PKA and Epac Signaling Pathways vol.9, pp.None, 2016, https://doi.org/10.3389/fphar.2018.00634
  2. Effects of different polyaniline emeraldine compositions in electrodepositing ginsenoside encapsulated poly(lactic‐co‐glycolic acid) microcapsules coating: Physicochemical characterization vol.108, pp.5, 2020, https://doi.org/10.1002/jbm.a.36891
  3. Traditional Herbal Medicine Discovery for the Treatment and Prevention of Pulmonary Arterial Hypertension vol.12, pp.None, 2021, https://doi.org/10.3389/fphar.2021.720873