Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia

Sharda Kumari; Susheel N Chaurasia; Manasa K Nayak; Ram L Mallick; Debabrata Dash

doi:10.1074/jbc.M114.615948

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Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia

Journal article

Open access

Peer reviewed

Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia

Sharda Kumari, Susheel N Chaurasia, Manasa K Nayak, Ram L Mallick and Debabrata Dash

The Journal of biological chemistry, Vol.290(19), pp.12290-12299

05/08/2015

DOI: 10.1074/jbc.M114.615948

PMCID: PMC4424360

PMID: 25829495

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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.

Animals

Annexin A5 - chemistry

Apoptosis

bcl-2-Associated X Protein - metabolism

Blood Platelets - cytology

Blood Platelets - metabolism

Cell Nucleus - metabolism

Flow Cytometry

Gene Expression Regulation

Humans

Macrophages - metabolism

Membrane Potentials

Mice

Phagocytosis

Platelet Count

Reactive Oxygen Species - metabolism

Sirtuin 1 - metabolism

Sirtuin 2 - metabolism

Sirtuin 3 - metabolism

Thrombocytopenia - blood

Thrombosis - metabolism

Details

Title: Subtitle: Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia
Creators: Sharda Kumari - Banaras Hindu University
Susheel N Chaurasia - Banaras Hindu University
Manasa K Nayak - Banaras Hindu University
Ram L Mallick - Banaras Hindu University
Debabrata Dash - Banaras Hindu University
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.290(19), pp.12290-12299
DOI: 10.1074/jbc.M114.615948
PMID: 25829495
PMCID: PMC4424360
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Language: English
Date published: 05/08/2015
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984359848302771

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