gyy-4137 and propargylglycine

A dual role of hydrogen sulfide (H

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Alkynes; Animals; Cell Differentiation; Gene Expression; Glycine; Hydrogen Sulfide; Inflammation; Mice; Morpholines; Organothiophosphorus Compounds; Sulfides

Infrarenal aortic cross-clamping (IAC) is a common procedure during infrarenal vascular operations. It often causes ischemia-reperfusion injury to lower limbs, resulting in systemic inflammation response and damage to remote organs (particularly lungs). Hydrogen sulfide (H. Wistar rats underwent IAC for 2 hours, followed by 4 hours of reperfusion. GYY4137 (a slow-releasing H. IAC induced a significant increase in plasma levels of H. The study indicates that H

Topics: Acute Lung Injury; Alkynes; Angiopoietin-2; Animals; Anti-Inflammatory Agents; Aorta, Abdominal; Constriction; Cystathionine gamma-Lyase; Cytoprotection; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Glycine; Hydrogen Sulfide; Lung; Lyases; Male; Morpholines; Organothiophosphorus Compounds; Pneumonia; Proto-Oncogene Proteins c-akt; Rats, Wistar

Structural remodeling of the microvasculature occurs during obesity. Based on observations that impaired H2S signaling is associated with cardiovascular pathologies, the current study was designed to test the hypothesis that altered H2S homeostasis is involved in driving the remodeling process in a diet-induced mouse model of obesity. The structural and passive mechanical properties of mesenteric resistance arterioles isolated from 30-wk-old lean and obese mice were assessed using pressure myography, and vessel H2S levels were quantified using the H2S indicator sulfidefluor 7-AM. Remodeling gene expression was assessed using quantitative RT-PCR, and histological staining was used to quantify vessel collagen and elastin. Obesity was found to be associated with decreased vessel H2S concentration, inward hypertrophic remodeling, altered collagen-to-elastin ratio, and reduced vessel stiffness. In addition, mRNA levels of fibronectin, collagen types I and III, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 1 were increased and elastin was decreased by obesity. Evidence that decreased H2S was responsible for the genetic changes was provided by experiments in which H2S levels were manipulated, either by inhibition of the H2S-generating enzyme cystathionine γ-lyase with dl-propargylglycine or by incubation with the H2S donor GYY4137. These data suggest that, during obesity, depletion of H2S is involved in orchestrating the genetic changes underpinning inward hypertrophic remodeling in the microvasculature.

Topics: Alkynes; Animals; Arterioles; Cells, Cultured; Collagen; Collagenases; Cystathionine gamma-Lyase; Diet, High-Fat; Disease Models, Animal; Elastin; Enzyme Inhibitors; Fibronectins; Gene Expression Regulation; Glycine; Hydrogen Sulfide; Hypertrophy; Male; Mesentery; Mice, Inbred C57BL; Morpholines; Obesity; Organothiophosphorus Compounds; Signal Transduction; Vascular Remodeling; Vascular Stiffness

Hydrogen sulfide (H2S) is an endogenous gaseous mediator that has gained increasing recognition as an important player in modulating acute and chronic inflammatory diseases. However, its role in virus-induced lung inflammation is currently unknown. Respiratory syncytial virus (RSV) is a major cause of upper and lower respiratory tract infections in children for which no vaccine or effective treatment is available. Using the slow-releasing H2S donor GYY4137 and propargylglycin (PAG), an inhibitor of cystathionine-γ-lyase (CSE), a key enzyme that produces intracellular H2S, we found that RSV infection led to a reduced ability to generate and maintain intracellular H2S levels in airway epithelial cells (AECs). Inhibition of CSE with PAG resulted in increased viral replication and chemokine secretion. On the other hand, treatment of AECs with the H2S donor GYY4137 reduced proinflammatory mediator production and significantly reduced viral replication, even when administered several hours after viral absorption. GYY4137 also significantly reduced replication and inflammatory chemokine production induced by human metapneumovirus (hMPV) and Nipah virus (NiV), suggesting a broad inhibitory effect of H2S on paramyxovirus infections. GYY4137 treatment had no effect on RSV genome replication or viral mRNA and protein synthesis, but it inhibited syncytium formation and virus assembly/release. GYY4137 inhibition of proinflammatory gene expression occurred by modulation of the activation of the key transcription factors nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3) at a step subsequent to their nuclear translocation. H2S antiviral and immunoregulatory properties could represent a novel treatment strategy for paramyxovirus infections.. RSV is a global health concern, causing significant morbidity and economic losses as well as mortality in developing countries. After decades of intensive research, no vaccine or effective treatment, with the exception of immunoprophylaxis, is available for this infection as well as for other important respiratory mucosal viruses. This study identifies hydrogen sulfide as a novel cellular mediator that can modulate viral replication and proinflammatory gene expression, both important determinants of lung injury in respiratory viral infections, with potential for rapid translation of such findings into novel therapeutic approaches for viral bronchiolitis and pneumonia.

Topics: Alkynes; Cell Line; Chemokines; Cystathionine gamma-Lyase; Enzyme Inhibitors; Glycine; Humans; Hydrogen Sulfide; Inflammation Mediators; Interferon Regulatory Factor-3; Morpholines; NF-kappa B; Organothiophosphorus Compounds; Paramyxoviridae Infections; Promoter Regions, Genetic; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Signal Transduction; Virus Replication

The exact etiology of preeclampsia is unknown, but there is growing evidence of an imbalance in angiogenic growth factors and abnormal placentation. Hydrogen sulfide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is a proangiogenic vasodilator. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension.. Plasma levels of H2S were significantly decreased in women with preeclampsia (P<0.01), which was associated with reduced placental CSE expression as determined by real-time polymerase chain reaction and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine reduced placental growth factorproduction from first-trimester (8-12 weeks gestation) human placental explants and inhibited trophoblast invasion in vitro. Knockdown of CSE in human umbilical vein endothelial cells by small-interfering RNA increased the release of soluble fms-like tyrosine kinase-1 and soluble endoglin, as assessed by enzyme-linked immunosorbent assay, whereas adenoviral-mediated CSE overexpression in human umbilical vein endothelial cells inhibited their release. Administration of DL-propargylglycine to pregnant mice induced hypertension and liver damage, promoted abnormal labyrinth vascularization in the placenta, and decreased fetal growth. Finally, a slow-releasing H2S-generating compound, GYY4137, inhibited circulating soluble fms-like tyrosine kinase-1 and soluble endoglin levels and restored fetal growth in mice that was compromised by DL-propargylglycine treatment, demonstrating that the effect of CSE inhibitor was attributable to inhibition of H2S production.. These results imply that endogenous H2S is required for healthy placental vasculature and that a decrease in CSE/H2S activity may contribute to the pathogenesis of preeclampsia.

Topics: Adolescent; Adult; Alkynes; Animals; Antigens, CD; Cells, Cultured; Cystathionine gamma-Lyase; Disease Models, Animal; Endoglin; Endothelium, Vascular; Female; Fetal Development; Glycine; Humans; Hydrogen Sulfide; Hypertension; Mice; Mice, Inbred C57BL; Morpholines; Neovascularization, Physiologic; Organ Culture Techniques; Organothiophosphorus Compounds; Placenta; Placenta Diseases; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Proteins; Pregnancy, Animal; Receptors, Cell Surface; Vascular Endothelial Growth Factor Receptor-1; Young Adult

Adipose tissue expressed endogenous cystathionine gamma lyase (CSE)/hydrogen sulfide (H2S) system. H2S precursor inhibited catecholamine stimulated lipolysis. Thus, we hypothesized that CSE/H2S system regulates lipolysis which contributed to the pathogenesis of insulin resistance.. We treated rat adipocyte with DL-propargylglycine (PAG, a CSE inhibitor), L-cysteine (an H2S precursor) plus pyridoxial phosphate (co-enzyme) or the H2S chronic release donor GYY4137, then the glycerol level was assayed for assessing the lipolysis. Then, the effects of PAG and GYY4137 on insulin resistance in high fatty diet (HFD) induced obese mice were investigated.. Here, we found that PAG time-dependently increased basal or isoproterenol stimulated lipolysis. However, L-cysteine plus pyridoxial phosphate or GYY4137 significantly reduced it. PAG increased phosphorylated protein kinase A substrate, perilipin 1 and hormone sensitive lipase, but L-cysteine and GYY4137 decreased the parameters. In HFD induced obese mice, PAG increased adipose basal lipolysis, thus blunted fat mass increase, resulting in lowering insulin resistance evidenced by reduction of fasting glucose, insulin level, HOMA index, oral glucose tolerance test (OGTT) curve area and elevating the insulin tolerance test (ITT) response. GYY4137 inhibited lipolysis in vivo without increasing fat mass, but also ameliorated the insulin resistance in HFD mice.. These results implicated that inhibition endogenous CSE/H2S system in adipocytes increased lipolysis by a protein kinase A-perilipin/hormone-sensitive lipase pathway, thus blunted fat mass increase and reduced insulin resistance in obese mice; giving H2S donor decreased lipolysis, also reduced insulin resistance induced by HFD. Our data showed that increase or decrease H2S induced opposite lipolysis, but had the same effect on insulin resistance. The paradoxical regulation may be resulted from different action of H2S on metabolic and endocrine function in adipocyte.

Topics: Adipocytes; Alkynes; Animals; Blood Glucose; Carrier Proteins; Cystathionine gamma-Lyase; Cysteine; Diet, High-Fat; Enzyme Inhibitors; Glycerol; Glycine; Hydrogen Sulfide; Insulin; Insulin Resistance; Isoproterenol; Lipolysis; Mice; Morpholines; Obesity; Organothiophosphorus Compounds; Perilipin-1; Phosphoproteins; Primary Cell Culture; Pyridoxal Phosphate; Rats; Sterol Esterase