title: Splitomicin suppresses human platelet aggregation via inhibition of cyclic AMP phosphodiesterase and intracellular Ca++ release.
abstract: Splitomicin is derived from beta-naphthol and is an inhibitor of Silent Information Regulator 2 (SIR2). Its naphthoic moiety might be responsible for its inhibitory effects on platelets. The major goal of our study was to examine possible mechanisms of action of splitomicin on platelet aggregation in order to promote development of a novel anti-platelet aggregation therapy for cardiovascular and cerebrovascular diseases. To study the inhibitory effects of splitomicin on platelet aggregation, we used washed human platelets, and monitored platelet aggregation and ATP release induced by thrombin (0.1 U/ml), collagen (2 microg/ml), arachidonic acid (AA) (0.5 mM), U46619 (2 microM) or ADP (10 microM). Splitomicin inhibited platelet aggregation induced by thrombin, collagen, AA and U46619 with a concentration dependent manner. Splitomicin increased cAMP and this effect was enhanced when splitomicin (150 microM) was combined with PGE1 (0.5 microM). It did not further increase cAMP when combined with IBMX. This data indicated that splitomicin increases cAMP by inhibiting activity of phosphodiestease. In addition, splitomicin (300 microM) attenuated intracellular Ca(++) mobilization, and production of thromboxane B2 (TXB2) in platelets that was induced by thrombin, collagen, AA or U46619. The inhibitory mechanism of splitomicin on platelet aggregation may increase cyclic AMP levels via inhibition of cyclic AMP phosphodiesterase activity and subsequent inhibition of intracellular Ca(++) mobilization, TXB2 formation and ATP release.
authors.affiliation: Department of Anesthesiology, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC.
authors.forename: Fu-Chao
authors.initials: FC
authors.lastname: Liu
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Liao
authors.forename: Yao-Wen
authors.initials: YW
authors.lastname: Chang
authors.forename: Jiin-Tarng
authors.initials: JT
authors.lastname: Liou
authors.forename: Yuan-Ji
authors.initials: YJ
authors.lastname: Day