Sirtuin inhibition induces apoptosis-like changes in platelets and thrombocytopenia

Abstract

Sirtuins are evolutionarily conserved NAD+-dependent acetyl-lysine deacetylases that belong to class III type of histone deacetylases. In humans, seven sirtuin isoforms (Sirt1 to Sirt7) have been identified. Sirtinol, a cell permeable lactone ring derived from naphthol, is a dual Sirt1/Sirt2 inhibitor of low potency whereas EX-527 is a potent and selective Sirt1 inhibitor. Here we have demonstrated that Sirt1, Sirt2 and Sirt3 are expressed in enucleate platelets. Both sirtinol or EX-527 induced apoptosis-like changes in platelets as revealed from enhanced annexin V binding, ROS production and drop in mitochondrial transmembrane potential. Above changes were associated with increased phagocytic clearance of the platelets by macrophages. Expression of acetylated p53 and the conformationally active form of Bax were found to be significantly higher in both sirtinol- as well as EX-527-treated platelets, thus implicating p53-Bax axis in apoptosis induced by sirtuin inhibitors. Administration of either sirtinol or EX-527 in mice led to reduction in both platelet count and number of reticulated platelets. Our results, for the first time, implicate sirtuins as a central player in determination of platelet aging. Since sirtuin inhibitors are being evaluated for their anti-tumor activity, this study rekindles attention to potential side effect of sirtuin inhibition in delimiting platelet life span and management of thrombosis.