Ginsenoside-Rp3 inhibits platelet activation and thrombus formation by regulating MAPK and cyclic nucleotide signaling

• DOI: 10.1016/j.vph.2018.06.002
• Publication Date: 2018-06-08T02:03:54Z
• Authors: Muhammad Irfan; Dahye Jeong; Hyuk-Woo Kwon; Jung-Hae Shin; Sang-Joon Park; Dongmi Kwak; Tae-Hwan Kim; Dong-Ha Lee; Hwa-Jin Park; Man Hee Rhee
• Keywords: Blood Platelets; Male; 0301 basic medicine; Dose-Response Relationship, Drug; Ginsenosides; Platelet Aggregation; MAP Kinase Signaling System; Phospholipase C gamma; Microfilament Proteins; Phosphoproteins; Platelet Activation; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; 03 medical and health sciences; Fibrinolytic Agents; Animals; Humans; Calcium Signaling; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinase; Phosphorylation; Cell Adhesion Molecules

Ginseng (Panax ginseng C.A. Mayer) contains saponin fractions called ginsenosides, which are thought to be the main components responsible for its various pharmacological activities. Ginsenosides have cardioprotective and antiplatelet effects. In the present study, we evaluated the effects of ginsenoside Rp3 (G-Rp3) on platelet function.The in vitro effects of G-Rp3 were evaluated on agonist-induced human and rat platelet aggregation, while [Ca2+]i mobilization, granule secretion, integrin αIIbβ3 activation, and clot retraction were assessed in rat platelets. Its effects on vasodilator-stimulated phosphoprotein (VASP) expression, phosphorylation of MAPK signaling molecules, and PI3K/Akt activation were also studied. Moreover, the tyrosine phosphorylation of components of the P2Y12 receptor downstream signaling pathway was also examined. The in vivo effects of G-Rp3 were studied using an acute pulmonary thromboembolism model and lung histopathology.G-Rp3 significantly inhibited collagen, ADP, and thrombin-induced platelet aggregation. G-Rp3 elevated cAMP levels and VASP phosphorylation and suppressed agonist-induced [Ca2+]i mobilization, ATP release, and P-selectin expression along with fibrinogen binding to integrin αIIbβ3, fibronectin adhesion, and clot retraction. G-Rp3 also attenuated the phosphorylation of MAPK, Src, and PLCγ2 as well as PI3K/Akt activation. Furthermore, it inhibited tyrosine phosphorylation of the Src family kinases (Src, Fyn, and Lyn) and PLCγ2 and protected mice from thrombosis.G-Rp3 modulates agonist-induced platelet activation and thrombus formation by inhibiting granule secretion, integrin αIIbβ3 activation, MAPK signaling, and Src, PLCγ2, and PI3K/Akt activation, and VASP stimulation. Our data suggest that G-Rp3 has therapeutic potential as a treatment for platelet-related cardiovascular disorders.