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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]

Accumulating evidence has suggested that hydrogen sulfide (H2S) is endogenously generated in many types of mammalian cells. Since H2S plays an important role in cardiovascular, central nervous and gastrointestinal systems, it is currently considered to be the third gaseous mediator. Recently, more and more attention has been paid to the biological functions of H2S in inflammation. In various animal models of inflammatory diseases (such as acute pancreatitis, sepsis and endotoxemia), endogenous H2S has been shown to be overproduced and participate in regulating the severity of inflammatory response and associated organ injury. Inhibition of H2S formation is likely to protect animals against these inflammatory diseases. H2S may exert its effect on inflammation via regulating the function of leukocytes, leukocyte trafficking and immune cell survival. Furthermore, H2S has been suggested to induce the release or production of neuropeptides (substance P and calcitonin gene-related peptide), which are considered to be pro-inflammatory mediators, and therefore contribute to inflammatory response. In addition, some studies reported that low doses of sodium hydrosulfide (NaHS, an H2S donor) exhibited some anti-inflammatory effect on local inflammation (such as non-steroidal anti-inflammatory drug-induced gastric injury). Taken together, all these findings demonstrate that in addition to the vasodilation and neuromodulation activity of H2S, it may contribute to the pathogenesis of inflammatory diseases via regulating the activation of leukocytes. [ABSTRACT FROM AUTHOR]

Increasing evidence has proposed that mitochondrial abnormalities may be an important factor contributing to the development of heart failure with preserved ejection fraction (HFpEF). Hydrogen sulfide (H 2 S) has been suggested to play a pivotal role in regulating mitochondrial function. Therefore, the present study was designed to explore the protective effect of H 2 S on mitochondrial dysfunction in a multifactorial mouse model of HFpEF. Wild type, 8-week-old, male C57BL/6J mice or cardiomyocyte specific- Cse (Cystathionine γ-lyase, a major H 2 S-producing enzyme) knockout mice (CSEcko) were given high-fat diet (HFD) and l -NAME (an inhibitor of constitutive nitric oxide synthases) or standardized chow. After 4 weeks, mice were randomly administered with NaHS (a conventional H 2 S donor), ZLN005 (a potent transcriptional activator of PGC-1α) or vehicle. After additional 4 weeks, echocardiogram and mitochondrial function were evaluated. Expression of PGC-1α, NRF1 and TFAM in cardiomyocytes was assayed by Western blot. Challenging with HFD and l -NAME in mice not only caused HFpEF but also inhibited the production of endogenous H 2 S in a time-dependent manner. Meanwhile the expression of PGC-1α and mitochondrial function in cardiomyocytes were impaired. Supplementation with NaHS not only upregulated the expression of PGC-1α, NRF1 and TFAM in cardiomyocytes but also restored mitochondrial function and ultrastructure, conferring an obvious improvement in cardiac diastolic function. In contrast, cardiac deletion of CSE gene aggravated the inhibition of PGC-1α-NRF1-TFAM pathway, mitochondrial abnormalities and diastolic dysfunction. The deleterious effect observed in CSEcko HFpEF mice was partially counteracted by pre-treatment with ZLN005 or supplementation with NaHS. Our findings have demonstrated that H 2 S ameliorates left ventricular diastolic dysfunction by restoring mitochondrial abnormalities via upregulating PGC-1α and its downstream targets NRF1 and TFAM, suggesting the therapeutic potential of H 2 S supplementation in multifactorial HFpEF. Schematic illustration of the protective effect of H 2 S on mitochondrial dysfunction in HF p EF and the underlying mechanism. [Display omitted] • The production of endogenous H 2 S was insufficient in a mouse model of HFpEF induced by mechanical and metabolic stress. • H 2 S improved mitochondrial function and alleviated HFpEF via upregulating PGC-1α, suggesting a therapeutic potential of H 2 S. • Cardiac deletion of Cse gene exacerbated diastolic dysfunction and mitochondrial abnormalities in HFpEF. [ABSTRACT FROM AUTHOR]

Objectives: Recent data in human and mice suggest that monocyte chemokine receptors CX3CR1 and CCR2 are involved in the pathogenesis of atherosclerosis. Our previous study showed that hydrogen sulfide, a novel gaseous mediator hampered the progression of atherosclerosis in fat-fed apoE mice with downregulating CX3CR1 and CX3CL1 expressions. However, there is a paucity of information regarding the clinical association between endogenous HS metabolism and alterations of monocyte chemokine receptors in patients with cardiovascular disease. Therefore, in this study, we investigated circulating monocyte heterogeneity with differential expressions of CCR2 and CX3CR1 and its relevance to plasma HS level in patients with coronary artery disease (CAD). Methods: Sixty-three CAD patients with acute coronary syndrome (ACS, n = 46) or stable angina pectoris (SAP, n = 17) undergoing either percutaneous coronary intervention or coronary angiography and eleven non-CAD patients were enrolled in the study. Plasma levels of HS as well as chemokines (CCL2 and CX3CL1) and expressions of CCR2 and CX3CR1 on peripheral monocytes were measured. Results: It was found that plasma HS level was significantly reduced, whereas plasma CCL2 and CX3CL1 levels were substantially elevated in patients with ACS, as compared with patients with SAP or non-CAD patients. Furthermore, patients with ACS had significantly higher proportion of CD14CCR2CX3CR1 and CD14CCR2CX3CR1 monocytes but lower percentage of CD14CCR2CX3CR1 monocytes than SAP or non-CAD patients did. Lastly, plasma HS level showed a significantly negative correlation with the proportion of CD14CCR2CX3CR1 monocytes, but not other monocyte subsets. Conclusions: These data indicate that decreased endogenous HS production may predispose stable CAD patients to rupture of vulnerable plaque and thus to ACS, probably in relation to circulating monocyte phenotypic transformation with differential expressions of CCR2 and CX3CR1. [ABSTRACT FROM AUTHOR]

Background Hydrogen sulfide (H 2 S), as a newly identified gaseous mediator, has been widely investigated in various systems. However, the effect of H 2 S 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 H 2 S on human platelet aggregation in vitro and its relevance to gap junction channels. Methods and results The antiaggregatory property of H 2 S-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 (100 μM), a conventional H 2 S 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 H 2 S is, at least in part, gap junction channel-dependent. Conclusions H 2 S may inhibit human platelet aggregation at least in part by depressing gap junction intercellular communication and H 2 S released from ACS14 may contribute to its additional anti-platelet effect in vitro in comparison to aspirin. [ABSTRACT FROM AUTHOR]

Abstract: We have earlier shown that mouse pancreatic acinar cells produce hydrogen sulfide (H2S), which plays a key role in the pathogenesis of acute pancreatitis (AP). H2S-dependent induction of inflammation is mediated by the activation of transcription factor NF-κB. We now provide evidence that activation of Src family kinases (SFKs) is crucial in signaling H2S-induced intracellular adhesion molecule (ICAM)-1 expression via NF-κB. Stimulation of acini with H2S resulted in a time-dependent activation of SFKs. In order to better understand this effect of H2S, acinar cells were stimulated with caerulein after addition of H2S donor, NaHS. Inhibition of SFKs impaired H2S-induced NF-κB activity and ICAM-1 expression in caerulein treated acinar cells. We also observed that H2S-induced up-regulation of ICAM-1 enhanced the adhesion of neutrophils onto acinar cells. Analysis of NF-κB pathway revealed that the effect of SFKs inhibition correlated with IκBα degradation and NF-κB DNA binding function. Interestingly, H2S-induced association of SFKs with translocation of NF-κB, and inhibition of SFKs prevented this response, indicating that this interaction may depend on activation of SFKs. These data suggest that H2S, by activating the phosphorylation of SFKs, may promote the transcriptional activity of NF-κB and eventually lead to an upregulation of ICAM-1 expression. [Copyright &y& Elsevier]