摘要
Thrombosis is a leading cause of mortality worldwide.As important gaseous signaling molecules,both nitric oxide(NO)and hydrogen sulfide(H_(2)S)demonstrate antiplatelet and anticoagulant functions,but little attention has been given to their synergistic effect and the underlying mechanism.In the present study,we developed an NO/H_(2)S codelivery system based on enzyme prodrug therapy(EPT)strategy in which the prodrugs are specif-ically recognized by the engineeredβ-galactosidase.Targeted codelivery of NO and H_(2)S in vivo was demonstrated by near-infrared fluorescence imaging and confirmed by measuring plasma and tissue levels;as a result,the side effects caused by systemic delivery,such as bleeding time,were reduced.Delivery of an optimized combination of NO and H_(2)S with a low combination index(CI)results in a synergistic effect on the inhibition of platelet adhesion and activation.Mechanistically,NO and H_(2)S cooperatively enhance the cGMP level through redoxbased posttranslational modifications of phosphodiesterase 5A(PDE5A),which leads to activation of the cGMP/PKG signaling pathway.Furthermore,targeted codelivery of NO and H_(2)S demonstrates enhanced thera-peutic efficacy for thrombosis in two mouse models of FeCl_(3)-induced arterial thrombosis and deep vein thrombosis.Collectively,these results confirm the synergistic efficacy of NO and H_(2)S for antithrombotic therapy,and the codelivery system developed in this study represents a promising candidate for clinical translation.
基金
supported by grants from the National Natural Sci-ence Foundation of China(Nos.81925021,82330066,U21A20391,823B2048,82370343)
Natural Science Foundation of Tianjin of China and the Natural Science Foundation of Heilongjiang Province of China(ZD2023H005).
