title: Ginsenoside-Rp1 inhibits platelet activation and thrombus formation via impaired glycoprotein VI signalling pathway, tyrosine phosphorylation and MAPK activation.
abstract: OBJECTIVE
  Ginsenosides are the main constituents for the pharmacological effects of Panax ginseng. Such effects of ginsenosides including cardioprotective and anti-platelet activities have shown stability and bioavailability limitations. However, information on the anti-platelet activity of ginsenoside-Rp1 (G-Rp1), a stable derivative of ginsenoside-Rg3, is scarce. We examined the ability of G-Rp1 to modulate agonist-induced platelet activation.
  
  
  METHODS
  G-Rp1 in vitro and ex vivo effects on agonist-induced platelet-aggregation, granule-secretion, [Ca(2+) ](i)  mobilization, integrin-α(IIb) β(3)  activation were examined. Vasodilator-stimulated phosphoprotein (VASP) and MAPK expressions and levels of tyrosine phosphorylation of the glycoprotein VI (GPVI) signalling pathway components were also studied. G-Rp1 effects on arteriovenous shunt thrombus formation in rats or tail bleeding time and ex vivo coagulation time in mice were determined. KEY RESULT: G-Rp1 markedly inhibited platelet aggregation induced by collagen, thrombin or ADP. While G-Rp1 elevated cAMP levels, it dose-dependently suppressed collagen-induced ATP-release, thromboxane secretion, p-selectin expression, [Ca(2+) ](i)  mobilization and α(IIb) β(3)  activation and attenuated p38(MAPK)  and ERK2 activation. Furthermore, G-Rp1 inhibited tyrosine phosphorylation of multiple components (Fyn, Lyn, Syk, LAT, PI3K and PLCγ2) of the GPVI signalling pathway. G-Rp1 inhibited in vivo thrombus formation and ex vivo platelet aggregation and ATP secretion without affecting tail bleeding time and coagulation time, respectively.
  
  
  CONCLUSIONS
  G-Rp1 inhibits collagen-induced platelet activation and thrombus formation through modulation of early GPVI signalling events, and this effect involves VASP stimulation, and ERK2 and p38(-MAPK)  inhibition. These data suggest that G-Rp1 may have therapeutic potential for the treatment of cardiovascular diseases involving aberrant platelet activation.
authors.affiliation: Laboratory of Physiology & Cell Signaling, College of Veterinary Medicine, Kyungpook National University, Daegu, Korea.
authors.forename: M
authors.initials: M
authors.lastname: Endale
authors.forename: W M
authors.initials: WM
authors.lastname: Lee
authors.forename: S M
authors.initials: SM
authors.lastname: Kamruzzaman
authors.forename: S D
authors.initials: SD
authors.lastname: Kim
authors.forename: J Y
authors.initials: JY
authors.lastname: Park
authors.forename: M H
authors.initials: MH
authors.lastname: Park
authors.forename: T Y
authors.initials: TY
authors.lastname: Park
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
authors.forename: J Y
authors.initials: JY
authors.lastname: Cho
authors.forename: M H
authors.initials: MH
authors.lastname: Rhee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D036145:Ginsenosides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000517:prevention & control; D013928:Thromboxane A2 / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D036145:Ginsenosides; D008840:Microfilament Proteins; D019007:P-Selectin; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C512675:ginsenoside Rp1; C098341:platelet membrane glycoprotein VI; D000098662:Vasodilator-Stimulated Phosphoprotein; D014443:Tyrosine; D013928:Thromboxane A2; D000255:Adenosine Triphosphate; D003094:Collagen; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D006152:Cyclic GMP; D002118:Calcium