A new insight of anti-platelet effects of sirtinol in platelets aggregation via cyclic AMP phosphodiesterase.
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 Ca(2+) 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 Ca(2+) mobilization, thromboxane A2 formation, and ATP release during the platelet aggregation.
Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou Taiwan, ROC.
Fu-Chao
FC
Liu
Chang-Hui
CH
Liao
Yao-Wen
YW
Chang
Jiin-Tarng
JT
Liou
Yuan-Ji
YJ
Day
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000527:Alprostadil / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009284:Naphthols / Q000737:chemistry / Q000494:pharmacology*; D019007:P-Selectin / Q000096:biosynthesis; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D013997:Time Factors
D001549:Benzamides; D009284:Naphthols; D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; C439060:sirtinol; D013929:Thromboxane B2; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000527:Alprostadil; D002118:Calcium