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Abstract: Hydrogen sulfide (H2S) is a novel gaseous mediator that plays important roles in atherosclerosis. The present study investigated the effect of a novel H2S-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 &y& Elsevier]