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A new insight of anti-platelet effects of sirtinol in platelets aggregation via cyclic AMP phosphodiesterase |
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| Authors: | Fu-Chao Liu Chang-Hui Liao Yao-Wen Chang Yuan-Ji Day |
| Institution: | a Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou Taiwan, ROC b Transgenic & Molecular Immunogenetics Laboratory, Chang Gung Memorial Hospital, Linkou Taiwan, ROC c Department of Medicine, Chang Gung University, Taiwan, ROC d Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan, ROC e Institution of Natural Products, Chang Gung University, Taiwan, ROC |
| Abstract: | Sirtinol, a cell permeable six-membered lactone ring, is derived from naphthol and potent inhibitor of SIR2 and its naphtholic may have the inhibitory effects on platelets aggregation. In this study, platelet function was examined by collagen/epinephrine (CEPI) and collagen/ADP-induced closure times using the PFA-100 system reveal that CEPI-CT and CADP-CT were prolonged by sirtinol. The platelets aggregation regulated by physiological agonists such as: thrombin, collagen and AA and U46619 were significantly inhibited by sirtinol. Increases cAMP level was observed when sirtinol treated with Prostaglandin E1 in washed platelets. Moreover, sirtinol attenuated intracellular Ca2+ release and thromboxane B2 formation stimulated by thrombin, collagen, AA and U46619 in human washed platelets. This study indicated that sirtinol could inhibit the platelet aggregation induced by physiological agonists, AA and U46619. The mechanism of action may include an increase of cAMP level with enhanced VASP-Ser157 phosphorylation via inhibition of cAMP phosphodiesterase activity and subsequent inhibition of intracellular Ca2+ mobilization, thromboxane A2 formation, and ATP release during the platelet aggregation. |
| Keywords: | SIR2 silent information regulator 2 TXB2 thromboxane B2 AA arachidonic acid HDAC histone deacetylase SIRT1 sirtuin1 FITC fluorescein isothiocyanate CEPI-CT collagen/epinephrine closure time CADP-CT collagen/ADP closure time PGE1 prostaglandin E1 cAMP cyclic adenosine monophosphate cGMP cyclic guanosine monophosphate ATP adenosine triphosphate ADP adenosine diphosphate SNP sodium nitroprusside IBMX 3-isobutyl-1-methylxanthine BSA bovine serum albumin EDTA ethylenediamine tetraacetic acid DMSO dimethylsulfoxide PRP platelet-rich plasma PPP platelet-poor plasma PKA protein kinase A PKG protein kinase G PDE phosphodiesterase EHNA erythro-9-(2-hydroxy-3-nonyl)adenine VASP vasodilator-stimulated phosphoprotein |
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