Effects Of S-propargyl-cysteine Research Articles

S-Propargyl-Cysteine Attenuates Diabetic Cardiomyopathy in db/db Mice Through Activation of Cardiac Insulin Receptor Signaling.

Background: Endogenous hydrogen sulfide (H2S) is emerging as a key signal molecule in the development of diabetic cardiomyopathy. The aim of this study was to explore the effect and underlying mechanism of S-propargyl-cysteine (SPRC), a novel modulator of endogenous H2S, on diabetic cardiomyopathy in db/db diabetic mice.Methods and Results: Vehicle or SPRC were orally administered to 8-month-old male db/db mice and their wild type littermate for 12 weeks. SPRC treatment ameliorated myocardial hypertrophy, fibrosis, and cardiac systolic dysfunction assessed by histopathological examinations and echocardiography. The functional improvement by SPRC was accompanied by a reduction in myocardial lipid accumulation and ameliorated plasma lipid profiles. SPRC treatment improved glucose tolerance in db/db mice, with fasting blood glucose and peripheral insulin resistance remaining unchanged. Furthermore, insulin receptor signaling involving the phosphorylation of protein kinase B (Akt/PKB) and glycogen synthase kinase 3β (GSK3β) were elevated and activated by SPRC treatment. Primary neonatal mice cardiomyocytes were cultured to explore the mechanisms of SPRC on diabetic cardiomyopathy in vitro. Consistent with the results in vivo, SPRC not only up-regulated insulin receptor signaling pathway in cardiomyocytes in dose-dependent manner in the basal state, but also relieved the suppression of insulin receptor signaling induced by high concentrations of glucose and insulin. Furthermore, SPRC also enhanced the expression of glucose transporter 4 (GLUT4) and 3H glucose uptake in cardiomyocytes.Conclusions: In this study, we found a novel beneficial effect of SPRC on diabetic cardiomyopathy, which was associated with activation of insulin receptor signaling. SPRC may be a promising medication for diabetic cardiomyopathy in type 2 diabetes mellitus patients.

O39 Gp130-mediated STAT3 activation by S-propargyl-cysteine, an endogenous hydrogen sulfide initiator, prevents doxorubicin-induced cardiotoxicity

Doxorubicin (Dox) could trigger a large amount of apoptotic cells in the myocardium, which leads to dilated cardiomyopathy and heart failure. S-propargyl-cysteine (SPRC), an endogenous hydrogen sulfide (H 2 S) initiator, possesses cardioprotective efficacy. However, the specific effect and mechanism of SPRC in Dox-induced cardiotoxicity remain elusive. Given gp130 with its main downstream signalling molecule, STAT3, is involved in cardiac myocyte survival and growth, the present study was performed to elucidate whether SPRC counteracts Dox-induced cardiotoxicity, and if so, whether the gp130/STAT3 pathway is involved in this cardioprotective activity. SPRC stimulated the activation of STAT3 via the gp130-mediated transduction tunnel in vitro and in vivo. In Dox-stimulated cardiotoxicity, SPRC enhanced cell viability, restored expression of gp130/STAT3-regulated downstream genes, inhibited apoptosis and oxidative stress, and antagonized mitochondrial dysfunction and intracellular Ca 2+ overload. Furthermore, blockade of gp130/STAT3 signalling abrogated all of the beneficial effects of SPRC. Our findings present the first piece of evidence for the therapeutic properties of SPRC in alleviating Dox cardiotoxicity, which could be attributed to the activation of gp130-mediated STAT3 signalling. This will offer a novel molecular basis and therapeutic strategy for the use of H 2 S donors in the treatment of heart failure.

S-Propargyl-Cysteine, a Novel Hydrogen Sulfide Donor, Inhibits Inflammatory Hepcidin and Relieves Anemia of Inflammation by Inhibiting IL-6/STAT3 Pathway.

Anemia of inflammation (AI) is clinically prevalent and greatly threatens public health. Traditional remedies have raised controversy during clinical practice, calling for alternative therapies. We have recently found that hydrogen sulfide (H2S) inhibits inflammatory hepcidin, the critical mediator of AI. However, due to the chemical property of H2S, there remains an urgent need for a stable H2S donor in AI treatment. Here we reported that S-propargyl-cysteine (SPRC), a novel water-soluble H2S donor, suppressed hepatic hepcidin and corrected hypoferremia induced by lipopolysaccharide. The effects of SPRC were reversed by inhibition of cystathionine γ-lyase, one of the major endogenous H2S synthases. Moreover, SPRC reduced serum hepcidin, improved transferrin saturation, and maintained erythrocyte membrane integrity in a chronic mouse AI model. Consistently, splenomegaly was ameliorated and splenic iron accumulation relieved. Mechanism study indicated that serum IL-6 content and hepatic Il-6 mRNA were decreased by SPRC, in parallel with reduced hepatic JAK2/STAT3 activation. On the whole, our data reveal the inhibition of inflammatory hepcidin by SPRC, and suggest SPRC as a potential remedy against AI.

P24 Cardioprotective effects of S-propargyl-cysteine controlled release formulation to heart failure rats after myocardial infarction and the possible involved mechanism

Background Heart failure (HF) is one of the most serious health issues in both developed and developing countries that causes millions of people suffering. In recent years, as a significant endogenous gasotransmitter, hydrogen sulfide has been reported to play vital roles on cardiovascular system. S-Propargyl-cysteine (SPRC), a novel endogenous hydrogen sulfide donor, is proved to mediate the formation of hydrogen sulfide to inhibit myocardial apoptosis and reduce oxidative stress to protect against acute myocardial ischemia. In order to produce more stable and sustaining hydrogen sulfide, we modified the dosage form to get SPRC controlled release formulation (SPRC (RS)). In this work, we elucidated the possible cardioprotective effects of this formulation on HF rats and investigated the involved mechanisms on apoptosis and oxidation. Methods Left coronary artery was occluded to induce HF model of rat. The survival rats were then divided into 7 groups (Sham, Model, SPRC, SPRC (RS), SPRC (RS)+PAG, PAG and Digoxin) after 24 h and treated with drugs for 6 weeks. Echocardiographic indexes including LV, LVID, LVPW, LVAW, EF and FS were recorded to determine the cardiac function. TTC staining was performed to determine the infarct size. Plasmatic level of hydrogen sulfide was detected by modified sulfide electrode. The enzymatic activities of SOD, CK, CAT and GSH were determined by colorimetry. The proteins extracted from myocardial tissues were determined by Western blot. Results The cardioprotective effects of SPRC (RS) on HF rats were confirmed by significant reduction of infarct size and improvement of cardiac function, with better effects than normal SPRC. LVAW, LVPW, FS and EF were elevated in SPRC (RS)-treated group compared with model group, while LV and LVID decreased. SPRC (RS) modulated antioxidant defenses in HF rats by preserving plasmatic levels of GSH, CAT and SOD and reducing CK leakage from cells. In addition, SPRC (RS) was shown to increase protein expression of Bcl-2 and decrease protein expression of Bax, caspase-3 and caspase-9 in infarct area to protect against myocardial apoptosis. Furthermore, SPRC (RS) promoted protein expression of CSE, then elevated plasmatic concentration of hydrogen sulfide. These effects of SPRC (RS) could be abolished by PAG, an inhibitor of CSE. Conclusion All experiment data indicated the SPRC controlled release formulation played a cardioprotective role on chronic heart failure after myocardial infarction, which was confirmed by improved cardiac function, decreased myocardial apoptosis and preserved oxidative stress. Endogenous hydrogen sulfide was partly involved in these protective effects of SPRC (RS). More important, SPRC (RS) exerted better effects than normal SPRC from all sides, that providing a new perspective on hydrogen sulfide-mediated drug therapy.

P43 Antioxidant and heart-protective effect of endogenous hydrogen sulfideon rats with streptozotocin-induced diabetes

Numerous studies have shown that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors especially oxidative stress. Hydrogen sulfide (H2S) has cardioprotective effects. This study was designed to investigate S-propargyl-cysteine (SPRC), an H2S donor, as well as its effect on the progression of heart-protective effectinStreptozotocin-Induced Diabetic Ratsand underlying mechanisms. Fifty male Sprague–Dawley Rats (5 groups, n = 10) were grouped into the normal control, diabetic control and low, moderate, and high doses of SPRC-treated groups. Six weeks later, SPRC-treated rats showed a significant alleviation in the development of heart dysfunction in a dose-dependent manner. Plasma H2S level and cystathionase-γ-lyase (CSE) activity in the ventricular tissues, determined by spectrophotometer, were significantly higher in SPRC-pretreated group. SPRC increased the Left ventricular mass index, the left ventricular systolic pressure and the maximum rate of pressure and decreased left ventricular end-diastolic pressure. In addition, Marginal changes in the lipid parameters were found in the SPRC-treated rats, with advanced glycation end products (AGES), triglyceride (TG) and high-density lipid cholesterol (HDL-C) elevation reduction at the high dose. In addition, SPRC also dose-dependently increased the total antioxidant capacities and in parallel decreased the lipid peroxidation levels in the serum and the left ventricular. The antioxidant effects of SPRC were implicated by the enhanced activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and levels of glutathione (GSH) in the serum, as well as the mRNA levels of CAT, SOD-1 and GPx in the left ventricular. On the other hand, SPRC treatmented dose-dependently reduced levels of serum lactate dehydrogenase (LDH) and malondialdehyde (MDA). In a streptozotocin-induced diabetic rat model, SPRC dose-dependently ameliorated the progression of cardiac vascular dysfunction accompanied by the suppression of oxidative stress. These findings suggested that SPRC might be a potential agent for the treatment of diabetic heart dysfunction. Download : Download full-size image

P13 S-Propargyl-Cysteine (SPRC) promoted angiogenesis under both normal and ischemic conditions: Possible STAT3-mediated mechanism

Background In most western countries, ischemic heart disease (IHD) is the most common cause of death and a major cause of hospital admissions. Conventional drug therapy is designed to effect through anti-oxidation, anti-apoptosis, anti-inflammation and anti-lipidemia to protect against IHD. Since hydrogen sulfide has been reported to induce angiogenesis in vitro and in vivo , we investigated the pro-angiogenic effect of SPRC, a novel water-soluble modulator of endogenous hydrogen sulfide, to provide experimental basis for angiogenesis-mediated drug therapy of IHD. In addition, we revealed STAT3-mediated mechanism involved in hydrogen sulfide-induced angiogenesis. Methods Cell viability assay, cell proliferation assay, cell adhesion assay, wound healing assay, transwell migration assay and tube formation assay were carried out to determine the pro-angiogenic effect of SPRC on endothelial cells in vitro . Matrigel plug assay, rat aortic ring assay, CAM assay and sponge implantation assay were carried out to determine the pro-angiogenic effect of SPRC in vivo . Hind-limb ischemia model and myocardial infarction model were induced to explore the angiogenesis in ischemic condition by laser doppler imaging and angiography. Western blot and immunofluorescence were used to detect the level and location of proteins, respectively. EMSA and CHIP were performed to determine the activation of STAT3 and its downstream promoters. Results SPRC promoted cell proliferation, adhesion, migration and tube formation of primary HUVEC and increased angiogenesis ex vivo and in vivo under both normal and ischemic conditions. In SPRC-induced angiogenesis, phosphorylation of VEGFR2 and STAT3 was elevated significantly, followed by activation of some signal molecules, such as MAPK and Akt. The interaction between VEGFR2 and STAT3 was enhanced after SPRC-treatment. Meanwhile, SPRC induced translocation of STAT3 to nucleus, followed by transcriptional activation of downstream promoters, especially vegf promoter. The critical roles of STAT3 in mediating the pro-angiogenic effect of SPRC were confirmed by RNA interference. Conclusion Based on the proved pro-angiogenic effect of hydrogen sulfide, we proposed and tested SPRC-induced angiogenesis in vitro and in vivo to provide experimental basis for angiogenesis-mediated drug therapy of IHD. More important, we investigated the relative mechanism of STAT3 involved in SPRC-induced angiogenesis, including interaction with VEGFR2 and translocation into nucleus to active transcription.

S-Propargyl-cysteine (SPRC) attenuated lipopolysaccharide-induced inflammatory response in H9c2 cells involved in a hydrogen sulfide-dependent mechanism

The present study attempts to investigate the effects of S-propargyl-cysteine (SPRC), a sulfur-containing amino acid, on lipopolysaccharide (LPS)-induced inflammatory response in H9c2 cardiac myocytes. We found that SPRC prevented nuclear factor-κB (NF-κB) activation assessed by NF-κB p65 phosphorylation and IκBα degradation, suppressed LPS-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and intracellular reactive oxygen species (ROS) production. Furthermore, incubation of H9c2 cells with SPRC induced phosphorylation of Akt in a time- and concentration-dependent manner. In addition, SPRC attenuated LPS-induced mRNA and protein expression of tumor necrosis factor-α (TNF-α), and mRNA expression of intercellular adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS). The effects of SPRC were abolished by cystathionine γ-lyase [CSE-an enzyme that synthesizes hydrogen sulfide (H(2)S)] inhibitor, DL: -propargylglycine (PAG), SPRC-induced Akt phosphorylation and TNF-α release was also abolished by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Furthermore, SPRC also increased LPS-induced down-regulation expression of CSE and H(2)S level in H9c2 cells. PAG abolished SPRC-induced up-regulation of H(2)S level. Therefore, we concluded that SPRC produced an anti-inflammatory effect in LPS-stimulated H9c2 cells partly through the CSE/H(2)S pathway by impairing IκBα/NF-κB signaling and by activating PI3K/Akt signaling pathway.