SHIP1 agonist rosiptor inhibits platelet activation and thrombosis by modulating cAMP/cGMP and PI3K/PKC pathway

Normal platelet activation is critical for proper hemostasis, while abnormal activation can lead to thrombotic diseases. Therefore, searching for substances that can regulate platelet activation will be helpful in preventing and treating thrombotic diseases. Studies have pointed out that SHIP1 can regulate platelet activation, affecting clot retraction and integrin αIIbβ3 activation. Nevertheless, the role of the SHIP1 agonist rosiptor in regulating platelet functions has not been investigated. This study aimed to investigate the antiplatelet and antithrombotic effects of rosiptor. Human platelets were isolated and used to evaluate the regulatory effect of rosiptor on platelet functions. The results showed that rosiptor significantly inhibits platelet activation, including aggregation, secretion, integrin αIIbβ3 activation, and Ca²⁺ mobilization. Moreover, rosiptor inhibited FeCl₃-induced mesenteric artery occlusive thrombus formation in mouse models in vivo. Notably, rosiptor did not significantly prolong tail bleeding time in mice. Mechanistically, the levels of cGMP and cAMP were measured using ELISA kits, and protein expression was detected by immunoblotting. Rosiptor enhanced cGMP and cAMP-dependent signal transduction and inhibited agonist-induced PI3K/PKC signaling pathway. In conclusion, our study suggests that rosiptor may have a potential therapeutic role in thrombotic diseases with a reduced risk of bleeding complications.