Browse > Article
http://dx.doi.org/10.3839/jabc.2019.014

Ginsenoside F4 inhibits platelet aggregation and thrombus formation by dephosphorylation of IP3RI and VASP  

Shin, Jung-Hae (Department of Biomedical Laboratory Science, Far East University)
Kwon, Hyuk-Woo (Department of Biomedical Laboratory Science, Far East University)
Lee, Dong-Ha (Department of Biomedical Laboratory Science, Namseoul University)
Publication Information
Journal of Applied Biological Chemistry / v.62, no.1, 2019 , pp. 93-100 More about this Journal
Abstract
The root of Panax ginseng is used in ethnomedicine throughout eastern Asia and various recent studies have proved that Panax ginseng has inhibitory effects on cardiovascular disease. Each factor causing cardiovascular disease is known to have a very complex process which is achieved by a diverse number of mechanisms. Among these factors, platelets are the most important because they directly participate in thrombogenesis. Therefore, inhibiting the activity of platelets is an essential element for prevention of cardiovascular diseases. Our previous study showed the antiplatelet effects of Korean red ginseng extract and two of its components, ginsenoside Rg3 and ginsenoside Ro. However, the inhibitory mechanism of other ginsenosides remains unclear. Therefore, we investigated the inhibitory mechanism of ginsenoside F4 (G-F4) from Korean red ginseng on the regulation of signaling molecules involved in human platelet aggregation. With the use of G-F4, collagen-induced human platelet aggregation was inhibited in a dose-dependent manner, and it suppressed collagen-induced elevation of $[Ca^{2+}]_i$ mobilization through elevated phosphorylation of inositol 1, 4, 5-triphosphate receptor I ($Ser^{1756}$). In addition, G-F4 inhibited fibrinogen binding to ${\alpha}IIb/{\beta}_3$ during collagen-induced human platelet aggregation. Thus, in the present study, G-F4 showed an inhibitory effect on human platelet activation, suggesting its potential use as a new natural medicine for preventing platelet-mediated cardiovascular diseases.
Keywords
Clot retraction; Ginsenoside F4; Inositol 1, 4, 5-triphosphate receptor I ($Ser^{1756}$); Vasodilator-stimulated phosphoprotein ($Ser^{157}$);
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Schwartz SM, Heimark RL, Majesky MW (1990) Developmental mechanisms underlying pathology of arteries. Physiol Rev 70: 1177-1209   DOI
2 Varga-Szabo D, Braun A, Nieswandt B (2009) Calcium signaling in platelets. J Thromb Haemost 7: 1057-1066   DOI
3 Schwarz UR, Walter U, Eigenthaler M (2001) Taming platelets with cyclic nucleotides. Biochem Pharmacol 62:1153-1161   DOI
4 Cavallini L, Coassin M, Borean A, Alexandre A (1996) Prostacyclin and sodium nitroprusside inhibit the activity of the platelet inositol 1,4,5-trisphosphate receptor and promote its phosphorylation. J Biol Chem 271: 5545-5551   DOI
5 Quinton TM, Dean WL (1992) Cyclic AMP-dependent phosphorylation of the inositol-1,4,5-trisphosphate receptor inhibits $Ca^{2+}$ release from platelet membranes. Biochemical and Biochem Biophys Res Commun 184: 893-899   DOI
6 Laurent V, Loisel TP, Harbeck B, Wehman A, Grobe L, Jockusch BM, Wehland J, Gertler FB, Carlier MF (1999) Role of proteins of the Ena/VASP family in actin-based motility of Listeria monocytogenes. J Cell Biol 144: 1245-1258   DOI
7 Sudo T, Ito H, Kimura Y (2003) Phosphorylation of the vasodilatorstimulated phosphoprotein (VASP) by the anti-platelet drug, cilostazol, in platelets. Platelets 14: 381-390   DOI
8 Ha YW, Lim SS, Ha IJ, Na YC, Seo JJ, Shin H, Kim YS (2007) Preparative isolation of four ginsenosides from Korean red ginseng (steam-treated Panax ginseng CA Meyer), by high-speed counter-current chromatography coupled with evaporative light scattering detection. J Chromatogr A 1151: 37-44   DOI
9 Park JD, Rhee DK, Lee YH (2005) Biological activities and chemistry of saponins from Panax ginseng CA Meyer. Phytochem Rev 4: 159-175   DOI
10 Chen B, Shen YP, Zhang DF, Cheng J, Jia XB (2013) The apoptosisinducing effect of ginsenoside F4 from steamed notoginseng on human lymphocytoma JK cells. Nat Prod Res 27: 2351-2354   DOI
11 Lee JH, Lim H, Shehzad O, Kim YS, Kim HP (2014) Ginsenosides from Korean red ginseng inhibit matrix metalloproteinase-13 expression in articular chondrocytes and prevent cartilage degradation. Eur J Pharmacol 724: 145-151   DOI
12 Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of $Ca^{2+}$ indicators with greatly improved fluorescence properties. J Biol Chem 260: 3440-3450   DOI
13 Shin JH, Kwon HW, Cho HJ, Rhee MH, Park HJ (2015) Inhibitory effects of total saponin from Korean red ginseng on $[Ca^{2+}]_i$ mobilization through phosphorylation of cyclic adenosine monophosphate-dependent protein kinase catalytic subunit and inositol 1, 4, 5-trisphosphate receptor type I in human platelets. J Ginseng Res 39: 354-364   DOI
14 Kwon HW, Shin JH, Cho HJ, Rhee MH, Park HJ (2016) Total saponin from Korean Red Ginseng inhibits binding of adhesive proteins to glycoprotein IIb/IIIa via phosphorylation of VASP (Ser157) and dephosphorylation of PI3K and Akt. J Ginseng Res 40: 76-85   DOI
15 Kuchay SM, Chishti AH (2007) Calpain-mediated regulation of platelet signaling pathways. Curr Opin Hematol 14: 249-254   DOI
16 Irfan M, Jeong DH, Kwon HW, Shin JH, Park SJ, Kwak D, Rhee MH (2018) Ginsenoside-Rp3 inhibits platelet activation and thrombus formation by regulating MAPK and cyclic nucleotide signaling. Vasc Pharmacol 109: 45-55   DOI
17 Smolenski A, Bachmann C, Reinhard K, Honig-Liedl P, Jarchau T, Hoschuetzky H, Walter U (1998) Analysis and regulation of vasodilatorstimulated phosphoprotein serine239 phosphorylation in vitro and in intact cells using a phosphor specific monoclonal antibody. J Biol Chem 273: 20029-20035   DOI
18 Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Commeau P, Comet B, Eigenthaler M (2003) Resistance to thienopyridines: Clinical detection of coronary stent thrombosis by monitoring of vasodilatorstimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 59: 295-302   DOI
19 Shin JH, Kwon HW, Cho HJ, Rhee MH, Park HJ (2016) Vasodilatorstimulated phosphoprotein-phosphorylation by ginsenoside Ro inhibits fibrinogen binding to ${\alpha}IIb/{\beta}3$ in thrombin-induced human platelets. J Ginseng Res 40: 359-365   DOI
20 Kwon HW (2018) 20 (S)-ginsenoside Rg3 inhibits glycoprotein IIb/IIIa activation in human platelets. J Appl Biol. Chem 61: 257-265   DOI
21 Azam M, Andrabi SS, Sahr KE, Kamath L, Kuliopulos A, Chishti AH (2001) Disruption of the mouse $\mu$-calpain gene reveals an essential role in platelet function. Mol Cell Biol 21: 2213-2220   DOI
22 Topol EJ, Byzova TV, Plow EF (1999) Platelet GPIIb-IIIa blockers. The Lancet 353: 227-231   DOI
23 Phillips DR, Nannizzi-Alaimo L, Prasad KS (2001) Beta3 tyrosine phosphorylation in alphaIIbbeta3 (platelet membrane GP IIb-IIIa) outside-in integrin signaling. Thromb Haemost 86: 246-258   DOI
24 Jackson SP (2011) Arterial thrombosis-insidious, unpredictable and deadly. Nature medicine 17: 1423-1436   DOI
25 Barrett NE, Holbrook L, Jones S, Kaiser WJ, Moraes LA, Rana R, Gibbins JM (2008) Future innovations in anti-platelet therapies. Brit J Pharmacol 154: 918-939   DOI
26 Payrastre B, Missy K, Trumel C, Bodin S, Plantavid M, Chap H (2000) The integrin alpha IIb/beta 3 in human platelet signal transduction. Biochem Pharmacol 60: 1069-1074   DOI