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Background: Hydrogen sulfide (H2S), as a newly identified gaseous mediator, has been widely investigated in various systems. However, the effect of H2S on cardiovascular system haemostasis, including platelet aggregation and the precise mechanisms remain unclear. Therefore, the present study was aimed to examine the inhibitory effect of H2S on human platelet aggregation in vitro and its relevance to gap junction channels., Methods and Results: The antiaggregatory property of H2S-releasing aspirin derivative (ACS14) was compared with its mother compound, aspirin. In comparison to an equimolar dose of aspirin, ACS14 not only exerted a more potent inhibitory effect on platelet aggregation induced by ADP or thrombin, but also significantly inhibited αIIbβ3 integrin activation and P-selectin expression. Similarly, NaHS (100μM), a conventional H2S donor significantly inhibited platelet aggregation as well as αIIbβ3 integrin activation and P-selectin expression induced by ADP or thrombin. Furthermore, pretreatment with rotigaptide, a gap junction modifier abolished the inhibitory properties of ACS14 or NaHS on platelet aggregation, suggesting that suppression of platelet aggregation by H2S is, at least in part, gap junction channel-dependent., Conclusions: H2S may inhibit human platelet aggregation at least in part by depressing gap junction intercellular communication and H2S released from ACS14 may contribute to its additional anti-platelet effect in vitro in comparison to aspirin., (Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Hydrogen sulfide (H(2)S) is a novel gaseous mediator that plays important roles in atherosclerosis. The present study investigated the effect of a novel H(2)S-releasing aspirin, ACS14 (2-acetyloxybenzoic acid 4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl ester), on atherosclerotic plaques in fat-fed apoE(-/-) mice and the underlying mechanism with respect to CX3C chemokine receptor 1 (CX3CR1) in macrophages. Mouse macrophage cell line RAW264.7 or mouse peritoneal macrophages were preincubated with aspirin (50, 100 or 200μM), ACS14 (50, 100 or 200μM) or vehicle for 6h, and then stimulated with interferon (IFN)-γ (500U/ml) or lipopolysaccharide (LPS; 10μg/ml) for 12h. ACS14, but not aspirin, dose-dependently inhibited IFN-γ or LPS-induced CX3CR1 expression and CX3CR1-mediated chemotaxis in macrophages. The inhibitory effect of ACS14 on CX3CR1 expression was abolished by pretreatment with GW9662, a selective peroxisome proliferator-activated receptor (PPAR)-γ antagonist, suggesting that suppression of macrophage CX3CR1 expression by ACS14 is PPAR-γ dependent. Eight-week-old male apoE(-/-) mice received intraperitoneal ACS14 (15 or 30μmol/kg/day) or aspirin (15 or 30μmol/kg/day) 4 weeks after fat feeding. Twelve weeks after ACS14 or aspirin treatment, mice were sacrificed to evaluate the extent of atherosclerosis and CX3CR1 expression in brachiocephalic artery (BCA). We found that ACS14, but not aspirin, significantly downregulated CX3CR1 expression in atherosclerotic plaques. ACS14 considerably impeded the formation and development of atherosclerosis as compared to a molar equivalent dose of aspirin. These data indicate that ACS14 may prevent the progression of atherosclerosis by downregulating macrophage CX3CR1 expression via a PPAR-γ-dependent mechanism., (Copyright © 2012 Elsevier B.V. All rights reserved.)