Journal of Ginseng Research

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

DOI QR Code

Korean red ginseng inhibits arginase and contributes to endothelium-dependent vasorelaxation through endothelial nitric oxide synthase coupling

  • Shin, Woosung (Department of Biology, College of Natural Sciences, Kangwon National University) ;
  • Yoon, Jeongyeon (Department of Biology, College of Natural Sciences, Kangwon National University) ;
  • Oh, Goo Taeg (Division of Life and Pharmaceutical Sciences, Ewha Womans University) ;
  • Ryoo, Sungwoo (Department of Biology, College of Natural Sciences, Kangwon National University)
  • Received : 2012.07.15
  • Accepted : 2012.09.02
  • Published : 2013.01.15
Download PDF
⟨ Previous Next ⟩

Abstract

Korean red ginseng water extract (KG-WE) has known beneficial effects on the cardiovascular system via inducting nitric oxide (NO) production in endothelium. Endothelial arginase inhibits the activity of endothelial nitric oxide synthase (eNOS) by substrate depletion, thereby reducing NO bioavailability and contributing to vascular diseases including hypertension, aging, and atherosclerosis. In the present study, we demonstrate that KG-WE inhibits arginase activity and negatively regulates NO production and reactive oxygen species generation in endothelium. This is associated with increased dimerization of eNOS without affecting the protein expression levels of either arginase or eNOS. In a vascular tension assay, when aortas isolated from wild type mice were incubated with KG-WE, NO-dependent enhanced vasorelaxation was observed. Furthermore, KG-WE administered via by drinking water to atherogenic model mice being fed high cholesterol diet improved impaired vascular function. Taken together, these results suggest that KG-WE may exert vasoprotective effects through augmentation of NO signaling by inhibiting arginase. Therefore, KG-WE may be useful in the treatment of vascular diseases derived from endothelial dysfunction, such as atherosclerosis.

Keywords

References

  1. Chevallier A. Encyclopedia of herbal medicine. New York: Dorling Kindersley, 2000.
  2. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-1693. https://doi.org/10.1016/S0006-2952(99)00212-9
  3. Cho WC, Chung WS, Lee SK, Leung AW, Cheng CH, Yue KK. Ginsenoside Re of Panax ginseng possesses significant antioxidant and antihyperlipidemic efficacies in streptozotocin-induced diabetic rats. Eur J Pharmacol 2006;550:173-179. https://doi.org/10.1016/j.ejphar.2006.08.056
  4. Helms S. Cancer prevention and therapeutics: Panax ginseng. Altern Med Rev 2004;9:259-274.
  5. Hu SY. A contribution to our knowledge of ginseng. Am J Chin Med (Gard City N Y) 1977;5:1-23. https://doi.org/10.1142/S0192415X77000026
  6. Lee TK, Johnke RM, Allison RR, O’Brien KF, Dobbs LJ Jr. Radioprotective potential of ginseng. Mutagenesis 2005;20:237-243. https://doi.org/10.1093/mutage/gei041
  7. Yuan HD, Kim JT, Kim SH, Chung SH: Ginseng and diabetes: the evidences from in vitro, animal and human studies. J Ginseng Res 2012; 36:27-39. https://doi.org/10.5142/jgr.2012.36.1.27
  8. Kim YM, Namkoong S, Yun YG, Hong HD, Lee YC, Ha KS, Lee H, Kwon HJ, Kwon YG, Kim YM. Water extract of Korean red ginseng stimulates angiogenesis by activating the PI3K/Akt-dependent ERK1/2 and eNOS pathways in human umbilical vein endothelial cells. Biol Pharm Bull 2007;30:1674-1679. https://doi.org/10.1248/bpb.30.1674
  9. Yu J, Eto M, Akishita M, Kaneko A, Ouchi Y, Okabe T. Signaling pathway of nitric oxide production induced by ginsenoside Rb1 in human aortic endothelial cells: a possible involvement of androgen receptor. Biochem Biophys Res Commun 2007;353:764-769. https://doi.org/10.1016/j.bbrc.2006.12.119
  10. Hien TT, Kim ND, Pokharel YR, Oh SJ, Lee MY, Kang KW. Ginsenoside Rg3 increases nitric oxide production via increases in phosphorylation and expression of endothelial nitric oxide synthase: essential roles of estrogen receptor-dependent PI3-kinase and AMP-activated protein kinase. Toxicol Appl Pharmacol 2010; Epub ahead of print.
  11. Wan JB, Lee SM, Wang JD, Wang N, He CW, Wang YT, Kang JX. Panax notoginseng reduces atherosclerotic lesions in ApoE-deficient mice and inhibits TNF-alpha-induced endothelial adhesion molecule expression and monocyte adhesion. J Agric Food Chem 2009;57:6692-6697. https://doi.org/10.1021/jf900529w
  12. Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC et al. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation 2003;108:2000-2006. https://doi.org/10.1161/01.CIR.0000092948.04444.C7
  13. Bivalacqua TJ, Hellstrom WJ, Kadowitz PJ, Champion HC. Increased expression of arginase II in human diabetic corpus cavernosum: in diabetic-associated erectile dysfunction. Biochem Biophys Res Commun 2001;283:923-927. https://doi.org/10.1006/bbrc.2001.4874
  14. Bivalacqua TJ, Liu T, Musicki B, Champion HC, Burnett AL. Endothelial nitric oxide synthase keeps erection regulatory function balance in the penis. Eur Urol 2007;51:1732-1740. https://doi.org/10.1016/j.eururo.2006.10.061
  15. Hsu LL, Champion HC, Campbell-Lee SA, Bivalacqua TJ, Manci EA, Diwan BA, Schimel DM, Cochard AE, Wang X, Schechter AN et al. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood 2007;109:3088-3098.
  16. Morris CR, Poljakovic M, Lavrisha L, Machado L, Kuypers FA, Morris SM Jr. Decreased arginine bioavailability and increased serum arginase activity in asthma. Am J Respir Crit Care Med 2004;170:148-153. https://doi.org/10.1164/rccm.200309-1304OC
  17. Nelin LD, Wang X, Zhao Q, Chicoine LG, Young TL, Hatch DM, English BK, Liu Y. MKP-1 switches arginine metabolism from nitric oxide synthase to arginase following endotoxin challenge. Am J Physiol Cell Physiol 2007;293:C632-C640. https://doi.org/10.1152/ajpcell.00137.2006
  18. Steppan J, Ryoo S, Schuleri KH, Gregg C, Hasan RK, White AR, Bugaj LJ, Khan M, Santhanam L, Nyhan D et al. Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism. Proc Natl Acad Sci U S A 2006;103:4759-4764. https://doi.org/10.1073/pnas.0506589103
  19. White AR, Ryoo S, Li D, Champion HC, Steppan J, Wang D, Nyhan D, Shoukas AA, Hare JM, Berkowitz DE. Knockdown of arginase I restores NO signaling in the vasculature of old rats. Hypertension 2006;47:245-251. https://doi.org/10.1161/01.HYP.0000198543.34502.d7
  20. Xu X, Gao X, Potter BJ, Cao JM, Zhang C. Anti-LOX-1 rescues endothelial function in coronary arterioles in atherosclerotic ApoE knockout mice. Arterioscler Thromb Vasc Biol 2007;27:871-877. https://doi.org/10.1161/01.ATV.0000259358.31234.37
  21. Woo A, Min B, Ryoo S. Piceatannol-3’-O-beta-D-glucopyranoside as an active component of rhubarb activates endothelial nitric oxide synthase through inhibition of arginase activity. Exp Mol Med 2010;42:524-532. https://doi.org/10.3858/emm.2010.42.7.053
  22. Ryoo S, Lemmon CA, Soucy KG, Gupta G, White AR, Nyhan D, Shoukas A, Romer LH, Berkowitz DE. Oxidized low-density lipoprotein-dependent endothelial arginase II activation contributes to impaired nitric oxide signaling. Circ Res 2006;99:951-960. https://doi.org/10.1161/01.RES.0000247034.24662.b4
  23. Ryoo S, Gupta G, Benjo A, Lim HK, Camara A, Sikka G, Lim HK, Sohi J, Santhanam L, Soucy K et al. Endothelial arginase II: a novel target for the treatment of atherosclerosis. Circ Res 2008;102:923-932. https://doi.org/10.1161/CIRCRESAHA.107.169573
  24. Andrawis N, Jones DS, Abernethy DR. Aging is associated with endothelial dysfunction in the human forearm vasculature. J Am Geriatr Soc 2000;48:193-198. https://doi.org/10.1111/j.1532-5415.2000.tb03911.x
  25. Demougeot C, Prigent-Tessier A, Marie C, Berthelot A. Arginase inhibition reduces endothelial dysfunction and blood pressure rising in spontaneously hypertensive rats. J Hypertens 2005;23:971-978. https://doi.org/10.1097/01.hjh.0000166837.78559.93
  26. Ming XF, Barandier C, Viswambharan H, Kwak BR, Mach F, Mazzolai L, Hayoz D, Ruffieux J, Rusconi S, Montani JP et al. Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation 2004;110:3708-3714. https://doi.org/10.1161/01.CIR.0000142867.26182.32
  27. Jin YR, Yu JY, Lee JJ, You SH, Chung JH, Noh JY, Im JH, Han XH, Kim TJ, Shin KS et al. Antithrombotic and antiplatelet activities of Korean red ginseng extract. Basic Clin Pharmacol Toxicol 2007;100:170-175. https://doi.org/10.1111/j.1742-7843.2006.00033.x
  28. Kwak YS, Kyung JS, Kim JS, Cho JY, Rhee MH. Anti-hyperlipidemic effects of red ginseng acidic polysaccharide from Korean red ginseng. Biol Pharm Bull 2010;33:468-472. https://doi.org/10.1248/bpb.33.468
  29. Park BJ, Lim YS, Lee HJ, Eum WS, Park J, Han KH, Choi SY, Lee KS. Anti-oxidative effects of Phellinus linteus and red ginseng extracts on oxidative stress-induced DNA damage. BMB Rep 2009;42:500-505. https://doi.org/10.5483/BMBRep.2009.42.8.500
  30. Wong VK, Cheung SS, Li T, Jiang ZH, Wang JR, Dong H, Yi XQ, Zhou H, Liu L. Asian ginseng extract inhibits in vitro and in vivo growth of mouse lewis lung carcinoma via modulation of ERK-p53 and NF-κB signaling. J Cell Biochem 2010;111:899-910. https://doi.org/10.1002/jcb.22778
  31. Kim CS, Park JB, Kim KJ, Chang SJ, Ryoo SW, Jeon BH. Effect of Korea red ginseng on cerebral blood flow and superoxide production. Acta Pharmacol Sin 2002;23:1152-1156.
  32. Kwok HH, Ng WY, Yang MS, Mak NK, Wong RN, Yue PY. The ginsenoside protopanaxatriol protects endothelial cells from hydrogen peroxide-induced cell injury and cell death by modulating intracellular redox status. Free Radic Biol Med 2010;48:437-445. https://doi.org/10.1016/j.freeradbiomed.2009.11.013
  33. Nakajima S, Uchiyama Y, Yoshida K, Mizukawa H, Haruki E. The effects of ginseng radix rubra on human vascular endothelial cells. Am J Chin Med 1998;26:365-373. https://doi.org/10.1142/S0192415X98000403
  34. Yang HN, Lee SE, Jeong SI, Park CS, Jin YH, Park YS. Up-regulation of heme oxygenase-1 by Korean red ginseng water extract as a cytoprotective effect in human endothelial cells. J Ginseng Res 2011;35:352-359. https://doi.org/10.5142/jgr.2011.35.3.352
  35. Jeon BH, Kim CS, Kim HS, Park JB, Nam KY, Chang SJ. Effect of Korean red ginseng on blood pressure and nitric oxide production. Acta Pharmacol Sin 2000;21:1095-1100.
  36. Persson IA, Dong L, Persson K. Effect of Panax ginseng extract (G115) on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) production. J Ethnopharmacol 2006;105:321-325. https://doi.org/10.1016/j.jep.2005.10.030
  37. Guan YY, Zhou JG, Zhang Z, Wang GL, Cai BX, Hong L, Qiu QY, He H. Ginsenoside-Rd from Panax notoginseng blocks Ca2+ influx through receptor- and store-operated Ca2+ channels in vascular smooth muscle cells. Eur J Pharmacol 2006;548:129-136. https://doi.org/10.1016/j.ejphar.2006.08.001
  38. Min JK, Kim JH, Cho YL, Maeng YS, Lee SJ, Pyun BJ, Kim YM, Park JH, Kwon YG. 20(S)-ginsenoside Rg3 prevents endothelial cell apoptosis via inhibition of a mitochondrial caspase pathway. Biochem Biophys Res Commun 2006;349:987-994. https://doi.org/10.1016/j.bbrc.2006.08.129
  39. He F, Guo R, Wu SL, Sun M, Li M. Protective effects of ginsenoside Rb1 on human umbilical vein endothelial cells in vitro. J Cardiovasc Pharmacol 2007;50:314-320. https://doi.org/10.1097/FJC.0b013e3180cab12e
  40. Leung KW, Pon YL, Wong RN, Wong AS. Ginsenoside-Rg1 induces vascular endothelial growth factor expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and beta-catenin/T-cell factor-dependent pathway in human endothelial cells. J Biol Chem 2006;281:36280-36288. https://doi.org/10.1074/jbc.M606698200
  41. Chicoine LG, Paffett ML, Young TL, Nelin LD. Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells. Am J Physiol Lung Cell Mol Physiol 2004;287:L60-L68. https://doi.org/10.1152/ajplung.00194.2003
  42. Zhang C, Hein TW, Wang W, Chang CI, Kuo L. Constitutive expression of arginase in microvascular endothelial cells counteracts nitric oxide-mediated vasodilatory function. FASEB J 2001;15:1264-1266. https://doi.org/10.1096/fj.00-0681fje
  43. North ML, Khanna N, Marsden PA, Grasemann H, Scott JA. Functionally important role for arginase 1 in the airway hyperresponsiveness of asthma. Am J Physiol Lung Cell Mol Physiol 2009;296:L911-L920.

Cited by

  1. Korean Red Ginseng Water Extract Restores Impaired Endothelial Function by Inhibiting Arginase Activity in Aged Mice vol.18, pp.2, 2014, https://doi.org/10.4196/kjpp.2014.18.2.95
  2. Daikenchuto (TU-100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K vol.4, pp.1, 2016, https://doi.org/10.1002/prp2.215
  3. Pharmacokinetics and Pharmacodynamics of Promising Arginase Inhibitors vol.42, pp.3, 2017, https://doi.org/10.1007/s13318-016-0381-y
  4. Korean Red Ginseng protects endothelial cells from serum-deprived apoptosis by regulating Bcl-2 family protein dynamics and caspase S-nitrosylation vol.37, pp.4, 2013, https://doi.org/10.5142/jgr.2013.37.413
  5. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases vol.38, pp.3, 2013, https://doi.org/10.1016/j.jgr.2014.03.001
  6. Vanillic acid in Panax ginseng root extract inhibits melanogenesis in B16F10 cells via inhibition of the NO/PKG signaling pathway vol.83, pp.7, 2013, https://doi.org/10.1080/09168451.2019.1606694
  7. Antihypertensive Effects of Rg3-Enriched Korean Vitamin Ginseng in Spontaneously Hypertensive Rats vol.15, pp.1, 2013, https://doi.org/10.1177/1934578x19900712
  8. Herbal Medicine for Cardiovascular Diseases: Efficacy, Mechanisms, and Safety vol.11, pp.None, 2013, https://doi.org/10.3389/fphar.2020.00422
  9. 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
  10. Adaptogenic effects of Panax ginseng on modulation of cardiovascular functions vol.44, pp.4, 2013, https://doi.org/10.1016/j.jgr.2020.03.001
  11. Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective vol.21, pp.15, 2020, https://doi.org/10.3390/ijms21155291
  12. Chemical components of ginseng, their biotransformation products and their potential as treatment of hypertension vol.476, pp.1, 2013, https://doi.org/10.1007/s11010-020-03910-8
  13. Ginsenosides for cardiovascular diseases; update on pre-clinical and clinical evidence, pharmacological effects and the mechanisms of action vol.166, pp.None, 2021, https://doi.org/10.1016/j.phrs.2021.105481