SIRT6 inhibits platelet activation and thrombosis by regulating PCSK9/MAPK signaling

Abstract

Abstract SIRT6 regulate metabolism related cardiovascular disease, however, whether SIRT6 is involved in thrombosis remains unclear. Immunoblotting result showed that the expression of SIRT6 in activated platelets was significantly lower than resting platelets. By using laser speckle with the mice receiving saline or SIRT6 agonist injection, we demonstrated that SIRT6 are required for platelet thrombus formation following FeCl3-induced arteriolar injury. To confirm a mechanistic role for SIRT6 in regulating platelet function and arterial thrombosis, we used SIRT6 knockout mice (SIRT6-/-) to verify the effect of SIRT6 deficiency on platelet activation and thrombosis in vitro and vivo. The results showed that SIRT6 deletion significantly increased platelet aggregation, release of dense particles as well α-particles, integrin αIIBβ3 activation and thrombosis, then SIRT6 abolished the effects of platelet activation and thrombosis. In a FeCl3-induced thrombosis model, we found that compared with WT mice, SIRT6-/- mice showed a significant contraction in time to occlusion. To eliminate the contribution of cells other to thrombosis formation, adoptive transfer experiments were carried out using isolated platelets, further indicated the importance of platelet SIRT6 in thrombosis. Mechanologically, we demonstrated that SIRT6 inhibits the potential of extracellular signal regulated kinase MAPK, which is associated with the PCSK9 and CD36 to enhance platelet activation. Taken together, these findings reveal the important role of SIRT6 in platelet function and thrombosis, and suggest that SIRT6 is a potential target for anti-thrombotic therapeutic intervention.