Abstract
Matrine is a naturally occurring alkaloid and possesses a wide range of pharmacological properties, such as anti-cancer, anti-oxidant, anti-inflammatory effects. However, whether it affects platelet function and thrombosis remains unclear. This study aims to evaluate the effect of matrine on platelet function and thrombus formation. Human platelets were treated with matrine (0–1 mg/ml) for 1 h at 37°C followed by measuring platelet aggregation, granule secretion, receptor expression by flow cytometry, spreading and clot retraction. In addition, matrine (10 mg/kg) was injected intraperitoneally into mice to measure tail bleeding time, arterial and venous thrombus formation. Matrine dose-dependently inhibited platelet aggregation and ATP release in response to either collagen-related peptide (Collagen-related peptide, 0.1 μg/ml) or thrombin (0.04 U/mL) stimulation without altering the expression of P-selectin, glycoprotein Ibα, GPVI, or αIIbβ3. In addition, matrine-treated platelets presented significantly decreased spreading on fibrinogen or collagen and clot retraction along with reduced phosphorylation of c-Src. Moreover, matrine administration significantly impaired the in vivo hemostatic function of platelets, arterial and venous thrombus formation. Furthermore, in platelets stimulated with CRP or thrombin, matrine significantly reduced Reactive oxygen species generation, inhibited the phosphorylation level of ERK1/2 (Thr202/Tyr204), p38 (Thr180/Tyr182) and AKT (Thr308/Ser473) as well as increased VASP phosphorylation (Ser239) and intracellular cGMP level. In conclusion, matrine inhibits platelet function, arterial and venous thrombosis, possibly involving inhibition of ROS generation, suggesting that matrine might be used as an antiplatelet agent for treating thrombotic or cardiovascular diseases.
Highlights
Platelets play key roles in pathological thrombosis and physiological hemostasis
Since thrombin might induce fibrinogen conversion to fibrin which might affect platelet agglutination, we evaluated matrine’s effect on fibrin formation in the absence of platelets using human platelet-deficient plasma and found that matrine did not affect fibrin formation induced by thrombin as shown by no difference of thrombin time after thrombin stimulation in the presence of difference doses of matrine (Supplementary Figure S1)
To further assess whether platelet dense-granule secretion is influenced by matrine, we simultaneously monitored ATP release during platelet aggregation induced by Collagen-related peptide (CRP) or thrombin and found that matrine significantly decreased ATP release from CRP- or thrombin-stimulated platelets in a dose-dependent manner (Figure 1B)
Summary
Platelets play key roles in pathological thrombosis and physiological hemostasis. In response to vascular injury, platelets will attach to the sub-endothelial matrix via recognition of exposed collagen and von Willebrand factor (VWF) by platelet surface adhesive receptors, glycoprotein (GP) Ib-IX-V and GPVI (Qiao et al, 2010; Qiao et al, 2018a). As the main bioactive compound in Kushen, matrine is a naturally occurring alkaloid and has been demonstrated to possess a wide range of pharmacological effects, such as anti-cancer, anti-oxidant, anti-inflammatory, antibacterial, anti-virus, and anti-fibrotic properties (You et al, 2020; Zhang et al, 2020). Due to these pharmacological properties, the role and effect of matrine has been investigated in several diseases, such as cardiovascular diseases (Yu et al, 2014; Zhang et al, 2021), liver diseases (Gao et al, 2018), autoimmune diseases (Zhao et al, 2011; Kan et al, 2015), or multiple cancers (Liu et al, 2014a). Considering the broad spectrum activities, whether matrine affects platelet function and thrombus formation remains poorly understood
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