Sanguinarine Attenuates Collagen-Induced Platelet Activation and Thrombus Formation.

Dan Shu,Yue Liu,Jiang-Bin Chen,Meng Lu,Xiang-Bin Zeng,Ding-Song Ye,Ying Zhu,Zhang-Yin Ming,Ao-Di He,Rong Ma

doi:10.3390/biomedicines9050444

Dan Shu, Yue Liu + Show 8 more

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https://doi.org/10.3390/biomedicines9050444

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Abstract

Sanguinarine, a benzophenanthridine alkaloid, has been described to have an antiplatelet activity. However, its antithrombotic effect and the mechanism of platelet inhibition have not thoroughly been explored. The current study found that sanguinarine had an inhibitory effect on thrombus formation. This inhibitory effect was quite evident both in the flow-chamber assays as well as in a murine model of FeCl3-induced carotid artery thrombosis. Further investigations also revealed that sanguinarine inhibited the collagen-induced human platelet aggregation and granule release. At the same time, it also prevented platelet spreading and adhesion to immobilized fibrinogen. The molecular mechanisms of its antiplatelet activity were found to be as follows: 1. Reduced phosphorylation of the downstream signaling pathways in collagen specific receptor GPVI (Syk-PLCγ2 and PI3K-Akt-GSK3β); 2. Inhibition of collagen-induced increase in the intracellular Ca2+ concentration ([Ca2+]i); 3. Inhibition of integrin αIIbβ3 outside-in signaling via reducing β3 and Src (Tyr-416) phosphorylation. It can be concluded that sanguinarine inhibits collagen-induced platelet activation and reduces thrombus formation. This effect is mediated via inhibiting the phosphorylation of multiple components in the GPVI signaling pathway. Current data also indicate that sanguinarine can be of some clinical value to treat cardiovascular diseases involving an excess of platelet activation.

Highlights

Platelets are discoid, anucleate cells that are continuously produced by megakaryocytes
As the arterial injury initially exposed the collagen under the endothelium, the current study focused on checking sanguinarine’s effect on collagen-induced human platelet aggregation
The results suggested that sanguinarine negatively regulated the phosphorylation of Syk-PLCγ2 and PI3K-Akt-GSK3β downstream of platelet GPVI

Summary

Introduction

Anucleate cells that are continuously produced by megakaryocytes. They are key factors during hemostasis and thrombosis, along with other physiological and pathological processes [1]. Epidemiological investigations indicate that several risk factors of thrombosis are related to high platelet activity and excessive activation of endothelial cell procoagulant functions. Abnormal platelet adhesion, aggregation, granule release and spreading can be the basis of thrombotic disease [2]. Thrombus is initiated by adhesion of platelet to collagen (via GPVI) and vWF (via GPIb-V-IX) [1]. Syk-PLCγ2 and PI3K-Akt signaling pathways are involved in collagen-activated platelets. It results in mobilization of cytoplasmic calcium, platelet

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