title: 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 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 demonstrate that Sirt1, Sirt2, and Sirt3 are expressed in enucleate platelets. Both sirtinol and EX-527 induced apoptosis-like changes in platelets, as revealed by enhanced annexin V binding, reactive oxygen species production, and drop in mitochondrial transmembrane potential. These 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- and EX-527-treated platelets, implicating the p53-Bax axis in apoptosis induced by sirtuin inhibitors. Administration of either sirtinol or EX-527 in mice led to a reduction in both platelet count and the number of reticulated platelets. Our results, for the first time, implicate sirtuins as a central player in the determination of platelet aging. Because sirtuin inhibitors are being evaluated for their antitumor activity, this study refocuses attention on the potential side effect of sirtuin inhibition in delimiting platelet life span and management of thrombosis.
authors.affiliation: From the Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Sharda
authors.initials: S
authors.lastname: Kumari
authors.affiliation: From the Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Susheel N
authors.initials: SN
authors.lastname: Chaurasia
authors.affiliation: From the Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Manasa K
authors.initials: MK
authors.lastname: Nayak
authors.affiliation: From the Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India.
authors.forename: Ram L
authors.initials: RL
authors.lastname: Mallick
authors.affiliation: From the Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India ddash.biochem@gmail.com.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Dash
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000737:chemistry; D017209:Apoptosis; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D010587:Phagocytosis; D010976:Platelet Count; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*; D056565:Sirtuin 2 / Q000378:metabolism*; D056566:Sirtuin 3 / Q000378:metabolism*; D013921:Thrombocytopenia / Q000097:blood*; D013927:Thrombosis / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D017304:Annexin A5; C494827:Bax protein, mouse; D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; D051028:bcl-2-Associated X Protein; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; C466093:SIRT3 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D056565:Sirtuin 2; D056566:Sirtuin 3
keywords: apoptosis; histone deacetylase (HDAC); platelet; sirtuin; thrombosis
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