Abstract
Atherothrombosis is one of the main underlying cause of cardiovascular diseases. In addition to treating atherothrombosis with antithrombotic agents, there is growing interest in the role of natural food products and biologically active ingredients for the prevention and treatment of cardiovascular diseases. This study aimed to investigate the effect of secolincomolide A (3) isolated from Lindera obtusiloba Blume on platelet activity and identify possible signaling pathways. In our study, the antiplatelet activities of 3 were measured by collagen-induced platelet aggregation and serotonin secretion in freshly isolated rabbit platelets. Interestingly, 3 effectively inhibited the collagen-induced platelet aggregation and serotonin secretion via decreased production of diacylglycerol, arachidonic acid, and cyclooxygenase-mediated metabolites such as thromboxane B2 (TXB2), and prostaglandin D2 (PGD2). In accordance with the antiplatelet activities, 3 prolonged bleeding time and attenuated FeCl3-induced thrombus formation in arterial thrombosis model. Notably, 3 abolished the phosphorylation of phospholipase Cγ2 (PLCγ2), spleen tyrosine kinase (Syk), p47, extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase B (Akt) by inhibiting the activation of the collagen receptor, glycoprotein VI (GPVI). Taken together, our results indicate the therapeutic potential of 3 in antiplatelet action through inhibition of the GPVI-mediated signaling pathway and the COX-1-mediated AA metabolic pathways.
Highlights
Platelets play crucial roles in physiological hemostatic and pathological thrombosis, leading to events of coronary heart disease and its associated complications (Stalker et al, 2012)
Expressed as a percentage of the control, collageninduced serotonin release was 28.13 and 82.68% (Figure 2B), and thrombin-induced serotonin release was 27.58 and 75.01% (Figure 2C) at 50 and 100 μM of 3, respectively. These results suggest that 3 exerts a strong inhibitory effect on collageninduced serotonin release after platelet activation leading to platelet aggregation
This study has two major findings: (1) 3 isolated from L. obtusiloba extract exhibited strong inhibitory effects on collagen-induced platelet aggregation and activation, and (2) the antiplatelet action of 3 occurs via inhibiting thrombotic metabolite formation and glycoprotein VI (GPVI)-mediated signaling pathway. This is the first report that 3 derived from L. obtusiloba extract acts on collagen receptor-mediated signal transduction mechanism and blocks the formation of COX-mediated products associated with platelet aggregation, leading to antiplatelet action
Summary
Platelets play crucial roles in physiological hemostatic and pathological thrombosis, leading to events of coronary heart disease and its associated complications (Stalker et al, 2012). Adhesive micromolecules and soluble platelet agonists, such as collagen, von Willebrand factor, adenosine diphosphate (ADP), and thrombin, are exposed or locally generated at the injury site (Steinhubl and Moliterno, 2005; Fogelson and Neeves, 2015). These molecules initiate platelet adhesion, activation, and aggregation to induce further thrombus formation. Prostaglandins include prostaglandin D2 (PGD2), thromboxane A2 (TXA2), and prostacyclines, and leukotrienes include cysteinyl leukotrienes and 12-hydroxyeicosatetraenoic acid (12-HETE) (Porro et al, 2014) Both COX and LOX metabolites are key mediators of vascular inflammation and atherothrombosis associated with platelet activation. Important role of TXA2 and 12-HETE have been suggested as pro-aggregatory factors in platelet function (Lee et al, 2014; Maskrey et al, 2014)
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