P104 Inhibition of platelet aggregation in vitro and in vivo by the H₂S releasing compound GYY4137

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• 作者：Michael Emerson^a ; Antonia Solomon^a ; Erica Smyth^a ; Mark E. Wood^b ; Matthew Whiteman^c
• 刊名：Nitric Oxide
• 出版年：30 May 2014
• 年：2014
• 卷：39
• 期：supp_S
• 页码：S47
• 全文大小：42 K

文摘

Platelets are key modulators of thrombotic events and a major target in the prevention of conditions including myocardial infarction. The role of H₂S in regulating platelets remains unclear with contradictory reports. The functional modulation of platelets by H₂S was investigated using light transmission aggregometry of isolated human platelets and in a mouse model for assessing aggregation of radiolabelled platelets in vivo. Additional biochemical assays determined the expression and activity of H₂S generating enzymes. Western blotting revealed that human platelets express the H₂S generating enzyme cystathione-beta synthase (CBS). Cystathione-gamma-lysase (CSE) was present at lower or undetectable levels. CBS activity was significantly higher in platelets compared to cell free samples whereas CSE was not active. Platelets were shown to generate H₂S using a fluorescent probe and H₂S production was significantly reduced by the CBS antagonist amino-oxyacetic acid. GYY4137 significantly reduced collagen-induced platelet aggregation in vitro and in vivo compared to control compound lacking the H₂S donating moiety. GYY4137 also enhanced NO-mediated inhibition of platelet aggregation in vitro, an effect that was shown to be mediated via soluble guanylyl cyclase. The ability of GYY4137 to inhibit platelet aggregation in vivo was attenuated in eNOS^−/− mice. Platelets therefore generate H₂S primarily via CBS. H₂S inhibits platelet aggregation and enhances the inhibitory actions of NO via cGMP-mediated signaling. H₂S therefore has potential physiological roles in platelets and as a putative therapeutic strategy in the treatment of platelet-driven disorders. We continue to develop and assess the effects of other novel H₂S donors including AP67 and AP72.