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The histone deacetylase sirtuin 2 is a new player in the regulation of platelet function
Author(s) -
Moscardó A.,
Vallés J.,
Latorre A.,
Jover R.,
Santos M. T.
Publication year - 2015
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13004
Subject(s) - sirt2 , platelet , acetylation , protein kinase b , phosphorylation , dense granule , chemistry , sirtuin , histone deacetylase , sirtuin 1 , microbiology and biotechnology , platelet activation , biochemistry , pharmacology , histone , biology , immunology , downregulation and upregulation , gene
Summary Background Histone deacetylases ( HDAC s) play a key role in signaling in many cell types. However, little is known about the participation of HDAC s, particularly sirtuins ( SIRT s), in platelet reactivity. Objective To investigate the role of HDAC s in platelets, we examined the effects of SIRT inhibition on platelet function and protein acetylation in human platelets. Methods We used washed platelets obtained from healthy subjects. Cambinol ( SIRT 1 and SIRT 2 inhibitor), AGK 2 (specific SIRT 2 inhibitor) and EX 527 (specific SIRT 1 inhibitor) were used as SIRT inhibitors. Platelets were stimulated with collagen, thrombin, or U46619, and platelet responses were determined according to optical aggregometry findings, dense granule release, and cytosolic calcium levels (Fura‐2 AM fluorescence). Protein acetylation and phosphorylation were assessed by immunoblotting. Results SIRT inhibition remarkably reduced platelet responses (aggregation, granule release, and cytosolic calcium level; P < 0.05). SIRT 2 was present in platelets at the level of mRNA and protein, and its specific inhibition reduced platelet responses. The acetylated protein pattern observed in resting platelets changed during platelet aggregation. Inhibition of SIRT 2 increased the acetylation of Akt kinase, which in turn blocked agonist‐induced Akt phosphorylation and glycogen synthase kinase‐3β phosphorylation, which are markers of Akt activity. Finally, collagen‐induced aggregation provoked Akt acetylation. Conclusions Regulation of protein acetylation by SIRT 2 plays a central role in platelet function. The effects of SIRT 2 are mediated in part by the acetylation and inhibition of Akt. These results open a new avenue for research into the control of platelet function, and may help to identify new therapeutic targets.