PB0815 - Mechanism of Bile acid in regulating platelet function and thrombotic diseases

Background: Platelet aggregation is essential for normal hemostatic process. However, aberrant platelet activation causes cardiovascular diseases such as thrombosis, atherosclerosis, and myocardial infarction. Therefore, it is particularly important to further study mechanisms of regulating platelet activation. Bile acids (BAs) play important roles in eliminating cholesterol and solubilizing lipid nutrients. However, the role of bile acids on platelets remains to be elaborated.

Aims: It’s significant to explore the functions of bile acids in platelet activation and clarify mechanisms of bile acids in platelet homeostasis.

Methods: Platelet aggregation and flow cytometric analysis were used to explore the role of BAs in platelet activation. Ferric chloride-induced carotid injury model was used to establish the influence of BAs on thrombus formation in mice. Proteomic analysis revealed the important role of noncatalytic region of tyrosine kinase (NCK1) in the inhibition of collagen-stimulated platelet activation by bile acids.

Results: We found that secondary bile acids have more inhibitory effects on platelet activation than primary bile acids, and among secondary bile acids, lithocholic acid (LCA) has the most significant inhibitory effect (Figure A). In the process of platelet activation, the inhibition of bile acid on Ca2+ internal flow exhibited a concentration - dependent effect. Bile acids suppressed platelet activation via Syk, PLCγ2, PI3K, Akt and ERK1/2 pathway. In addition, we found that NCK1 deficiency significantly suppresses the activity of platelets, and inhibits arterial thrombosis (Figure B-E). Phosphorylated proteomics analysis revealed that phosphorylation at the serine site of Syntaxin-11 was inhibited by LCA in platelet, suggesting that Syntaxin-11 may play an important role in platelet activation.

Conclusion(s): Bile acids play critical roles in platelet activation via Syk, PLCγ2, PI3K, Akt and ERK1/2 pathway, which was associated with NCK1. Anti-platelet studies of bile acids provide theoretical basis for the development of new antiplatelet agents.