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Timosaponin AIII induces antiplatelet and antithrombotic activity via Gq-mediated signaling by the thromboxane A2 receptor
- Source :
- Scientific Reports
- Publication Year :
- 2016
- Publisher :
- Nature Publishing Group, 2016.
-
Abstract
- The thromboxane (Tx) A2 pathway is a major contributor to the amplification of initial platelet activation and is therefore a key drug target. To identify potent small-molecule inhibitors of the thromboxane prostaglandin (TP) receptor, we screened a small steroidal saponin library using U46619-induced rat platelet aggregation assays. Timosaponin AIII (TAIII) was identified as a potent inhibitor of U46619-induced rat platelet aggregation and exhibited superior selectivity for the TP receptor versus other G protein-coupled receptors and a PKC activator. TAIII inhibited U46619-induced rat platelet aggregation independent of increases in cAMP and cGMP and the inhibition of TxA2 production. Both PKC and PLC activators restored TAIII-inhibited platelet aggregation, whereas TAIII did not inhibit platelet aggregation induced by co-activation of the G12/13 and Gz pathways. Furthermore, TAIII did not affect the platelet shape change or ROCK2 phosphorylation evoked by low-dose U46619. In vivo, TAIII prolonged tail bleeding time, reduced the mortality of animals with acute pulmonary thromboembolism and significantly reduced venous thrombus weight. Our study suggests that TAIII, by preferentially targeting Gq-mediated PLC/PKC signaling from the TP receptor, induces stronger in vitro antiplatelet activity and in vivo antithrombotic effects and may be an excellent candidate for the treatment of thrombotic disorders.
- Subjects :
- Blood Platelets
Male
0301 basic medicine
medicine.medical_specialty
Thromboxane
Prostaglandin
030204 cardiovascular system & hematology
Antithrombins
Receptors, Thromboxane A2, Prostaglandin H2
Article
Mice
Thromboxane A2
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Internal medicine
Cyclic AMP
medicine
Animals
Platelet
Platelet activation
Rats, Wistar
Receptor
Cyclic GMP
Protein kinase C
Mice, Inbred BALB C
Multidisciplinary
Chemistry
Drug Synergism
Saponins
Rats
030104 developmental biology
Endocrinology
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
GTP-Binding Protein alpha Subunits, Gq-G11
Platelet aggregation inhibitor
Steroids
Platelet Aggregation Inhibitors
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....6eafe9a6586aaa83e6d8eea7a25a664d
- Full Text :
- https://doi.org/10.1038/srep38757