Abstract
Background: Xinmailong (XML), a bioactive composite extracted from Periplaneta americana, has been widely used to treat cardiovascular diseases such as congestive heart failure. However, it is unclear whether XML has antiplatelet and antithrombotic effects. Methods: The effects of XML on agonist-induced platelet aggregation, adhesion and spreading, granule secretion, integrin α II bβ3 activation, and thrombus formation were evaluated. Phosphorylation of Syk, PLCγ2, Akt, GSK3β, and MAPK signaling molecules was also studied on agonist-induced platelets. In addition, the antithrombotic effects of XML were observed in vivo using an acute pulmonary thrombosis mouse model. Results: XML dose-dependently inhibited in vitro platelet aggregation and granule secretion induced by thrombin, collagen, and arachidonic acid (AA). XML also greatly reduced platelet adhesion and spreading on both collagen- and fibrinogen-coated surfaces. Biochemical analysis revealed that XML inhibited thrombin-, collagen-, and AA-induced phosphorylation of Syk, PLCγ2, Akt, GSK3β, and MAPK. Additionally, XML significantly inhibited in vivo thrombus formation in a collagen–epinephrine-induced acute pulmonary thrombosis mouse model. Conclusions and General Significance: Here, we provide the first report showing that XML inhibits platelet function and that it possesses antithrombotic activity. This suggests that XML could be a potential therapeutic candidate to prevent or treat platelet-related cardiovascular diseases.
Highlights
Thrombotic diseases, such as stroke, myocardial infarction, and arteriosclerosis have become the primary cause of death in humans, and platelets play crucial roles both in physiological hemostasis and pathological thrombosis (Michelson, 2010)
XML (0.1 mg/ml, 1 mg/ml, 10 mg/ml) exhibited a dosedependent inhibitory effect on platelet aggregation stimulated by collagen (1 μg/ml), thrombin (0.04 U/ml), and arachidonic acid (AA) (62.5 μM) in human Platelet-rich plasma (PRP) (Figure 3A); 1 mg/ml XML significantly decreased collagen-induced platelet aggregation to 44.0 ± 2.3% from 66.0 ± 3.3% (n = 4; P < 0.01), thrombin-induced platelet aggregation to 26.0 ± 1.7% from 53.0 ± 0.6% (n = 4; P < 0.01), and AA-induced platelet aggregation to 34.0 ± 2.2% from 41.0 ± 1.9% (n = 4; P < 0.05). 10 mg/ml XML almost fully abolished thrombininduced platelet aggregation (5.0 ± 2.0%) and AA-induced platelet aggregation (8.0 ± 1.3%) and decreased collageninduced platelet aggregation to 18.0 ± 0%
In washed human platelets, XML (0.1, 1, 10 mg/ml) exhibited a dosedependent inhibitory effect on platelet aggregation stimulated by collagen (1 μg/ml), thrombin (0.04 U/ml), and AA (62.5 μM) (Figure 3B)
Summary
Thrombotic diseases, such as stroke, myocardial infarction, and arteriosclerosis have become the primary cause of death in humans, and platelets play crucial roles both in physiological hemostasis and pathological thrombosis (Michelson, 2010). Activated integrin α II bβ can bind soluble ligands such as fibrinogen and von Willebrand factor (vWF) and subsequently mediate “outside-in” integrin signaling, which leads to integrin clustering, changes in platelet morphology, and postoccupancy events (Mehrbod et al, 2013). These signaling events are responsible for stimulating platelet adhesion and thrombus growth via influencing processes such as clot retraction, platelet aggregation, and platelet spreading (Shattil, 1999). It is unclear whether XML has antiplatelet and antithrombotic effects
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