H 2 S Protects Against Methionine–Induced Oxidative Stress in Brain Endothelial Cells (original) (raw)
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Endothelial Dysfunction: The Link Between Homocysteine and Hydrogen Sulfide
Current Medicinal Chemistry, 2014
High level of homocysteine (hyperhomocysteinemia, HHcy) is associated with increased risk for vascular disease. Evidence for this emerges from epidemiological studies which show that HHcy is associated with premature peripheral, coronary artery and cerebrovascular disease independent of other risk factors. Possible mechanisms by which homocysteine causes vascular injury include endothelial injury, DNA dysfunction, proliferation of smooth muscle cells, increased oxidative stress, reduced activity of glutathione peroxidase and promoting inflammation. HHcy has been shown to cause direct damage to endothelial cells both in vitro and in vivo. Clinically, this manifests as impaired flow-mediated vasodilation and is mainly due to a reduction in nitric oxide synthesis and bioavailability. The effect of impaired nitric oxide release can in turn trigger and potentiate atherothrombogenesis and oxidative stress. Endothelial damage is a crucial aspect of atherosclerosis and precedes overt manifestation of disease. In addition, endothelial dysfunction is also associated with hypertension, diabetes, ischemia reperfusion injury and neurodegenerative diseases. Homocysteine is a precursor of hydrogen sulfide (H 2 S) which is formed by transulfuration process catalyzed by the enzymes, cystathionine β-synthase and cystathionine γlyase. H 2 S is a gasotransmitter that has emerged recently as a novel mediator in cardiovascular homeostasis. As a potent vasodilator, it plays several roles which include regulation of vessel diameter, protection of endothelium from redox stress, ischemia reperfusion injury and chronic inflammation. However, the precise mechanism by which it mediates these beneficial effects is complex and still remains unclear. Current evidence indicates H 2 S modulates cellular functions by a variety of intracellular signaling processes. In this review, we summarize the mechanisms of HHcy-induced endothelial dysfunction and the metabolism and physiological functions of H 2 S as a protective agent.
Archiv für Experimentelle Pathologie und Pharmakologie
The aim of this study was to examine the ability of H2S, released from NaHS to protect vascular endothelial function under conditions of acute oxidative stress by scavenging superoxide anions (O2 (-)) and suppressing vascular superoxide anion production. O2 (-) was generated in Krebs' solution by reacting hypoxanthine with xanthine oxidase (Hx-XO) or with the O2 (-) generator pyrogallol to model acute oxidative stress in vitro. O2 (-) generation was measured by lucigenin-enhanced chemiluminescence. Functional responses in mouse aortic rings were assessed using a small vessel myograph. NaHS scavenged O2 (-) in a concentration-dependent manner. Isolated aortic rings exposed to either Hx-XO or pyrogallol displayed significantly attenuated maximum vasorelaxation responses to the endothelium-dependent vasodilator acetylcholine, and significantly reduced NO bioavailability, which was completely reversed if vessels were pre-incubated with NaHS (100 μM). NADPH-stimulated aortic O2 (-) p...
H2S and its role in redox signaling
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2014
Hydrogen sulfide (H 2 S) has emerged as an important gaseous signaling molecule that is produced endogenously by enzymes in the sulfur metabolic network. H 2 S exerts its effects on multiple physiological processes important under both normal and pathological conditions. These functions include neuromodulation, regulation of blood pressure and cardiac function, inflammation, cellular energetics and apoptosis. Despite the recognition of its biological importance and its beneficial effects, the mechanism of H 2 S action and the regulation of its tissue levels remain unclear in part owing to its chemical and physical properties that render handling and analysis challenging. Furthermore, the multitude of potential H 2 S effects has made it difficult to dissect its signaling mechanism and to identify specific targets. In this review, we focus on H 2 S metabolism and provide an overview of the recent literature that sheds some light on its mechanism of action in cellular redox signaling in health and disease. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.
Hyperhomocysteinemia’s effect on antioxidant capacity in rats
Central European Journal of Medicine, 2010
Hyperhomocysteinemia represents elevated homocysteine (Hcys) concentrations in blood above the normal range. In humans, the normal range of homocysteine is 5.0–15.9 mM/ml. High levels of homocysteine disturb the normal epithelial functions and correlate with cardiovascular diseases even at slightly increased concentrations. In homocysteine metabolism, vitamins play an important role. The mechanism through which homocysteine triggers these effects is not yet elucidated, but the involvement of reactive species may be the answer. It is not known whether the intra- or extracellular antioxidant system is more affected by elevated homocysteine levels. We studied the effects of hyperhomocysteinemia on the intra- and extracellular antioxidant defense systems in two different types of diet in rats. Type I was food with low folic acid and vitamin B12 content and type II was food with normal amounts of these two vitamins. Hyperhomocysteinemia was experimentally induced by oral administration of methionine 2 mg/kg body weight, single daily dose, for a 15-day period. Plasma concentrations of homocysteine were measured using an HPLC method. In the response of the intracellular antioxidant defense system against hyperhomocysteinemia, we determined the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in red blood cells, using RANDOX kits for manual use. For the extracellular response we determined the plasma total antioxidant status (TAS) also using a RANDOX kit for manual use. Our data show that methionine load induces hyperhomocysteinemia despite normal vitamin supply in rats. SOD activity rose with simultaneous decrease in GPx activity independently of diet; this might suggest that the intracellular defense system was disturbed by the rise in homocysteine level. TAS decrease suggests that the extracellular antioxidant defense was also affected. We assume that hyperhomocysteinemia is directly linked to reactive species generation and the intracellular space seems to be more affected than the extracellular one.
Oxidative Medicine and Cellular Longevity, 2018
Maternal high levels of the redox active amino acid homocysteine-called hyperhomocysteinemia (hHCY)-can affect the health state of the progeny. The effects of hydrogen sulfide (H 2 S) treatment on rats with maternal hHCY remain unknown. In the present study, we characterized the physical development, reflex ontogeny, locomotion and exploratory activity, muscle strength, motor coordination, and brain redox state of pups with maternal hHCY and tested potential beneficial action of the H 2 S donor-sodium hydrosulfide (NaHS)-on these parameters. Our results indicate a significant decrease in litter size and body weight of pups from dams fed with methionine-rich diet. In hHCY pups, a delay in the formation of sensory-motor reflexes was observed. Locomotor activity tested in the open field by head rearings, crossed squares, and rearings of hHCY pups at all studied ages (P8, P16, and P26) was diminished. Exploratory activity was decreased, and emotionality was higher in rats with hHCY. Prenatal hHCY resulted in reduced muscle strength and motor coordination assessed by the paw grip endurance test and rotarod test. Remarkably, administration of NaHS to pregnant rats with hHCY prevented the observed deleterious effects of high homocysteine on fetus development. In rats with prenatal hHCY, the endogenous generation of H 2 S brain tissues was lower compared to control and NaHS administration restored the H 2 S level to control values. Moreover, using redox signaling assays, we found an increased level of malondialdehyde (MDA), the end product of lipid peroxidation, and decreased activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the brain tissues of rats of the hHCY group. Notably, NaHS treatment restored the level of MDA and the activity of SOD and GPx. Our data suggest that H 2 S has neuroprotective/antioxidant effects against homocysteine-induced neurotoxicity providing a potential strategy for the prevention of developmental impairments in newborns.
International Journal of Developmental Neuroscience, 2011
The purpose of this study was to develop a chronic chemically induced model of mild hyperhomocysteinemia in adult rats. We produced levels of Hcy in the blood (30 M), comparable to those considered a risk factor for the development of neurological and cardiovascular diseases, by injecting homocysteine subcutaneously (0.03 mol/g of body weight) twice a day, from the 30th to the 60th postpartum day. Controls received saline in the same volumes. Using this model, we evaluated the effect of chronic administration of homocysteine on redox status in the blood and cerebral cortex of adult rats. Reactive oxygen species and thiobarbituric acid reactive substances were significantly increased in the plasma and cerebral cortex, while nitrite levels were reduced in the cerebral cortex, but not in the plasma, of rats subjected to chronic mild hyperhomocysteinemia. Homocysteine was also seen to disrupt enzymatic and non-enzymatic antioxidant defenses in the blood and cerebral cortex of rats. Since experimental animal models are useful for understanding the pathophysiology of human diseases, the present model of mild hyperhomocysteinemia may be useful for the investigation of additional mechanisms involved in tissue alterations caused by homocysteine.
Toxicology, 2004
A number of scavengers of reactive oxygen species (ROS) were found to be protective against cell death induced by hydrogen sulfide (H 2 S) in isolated hepatocytes. The H 2 O 2 scavengers ␣-ketoglutarate and pyruvate, which also act as energy substrate metabolites, were more protective against H 2 S toxicity than lactate which is only an energy substrate metabolite. All of these results suggest that H 2 S toxicity is dependent on ROS production. We measured ROS formation directly in hepatocytes using the fluorogenic dichlorofluorescin method. H 2 S-induced ROS formation was dose dependent and pyruvate inhibited this ROS production. Non-toxic concentrations of H 2 S enhanced the cytotoxicity of H 2 O 2 generated by glucose/glucose oxidase, which was inhibited by CYP450 inibitors. Furthermore, hepatocyte ROS formation induced by H 2 S was decreased by CYP450 inhibitors cimetidine and benzylimidazole. These results suggest that CYP450-dependant metabolism of H 2 S is responsible for inducing ROS production. H 2 S-induced cytotoxicity was preceded by mitochondrial depolarization as measured by rhodamine 123 fluorescence. Mitochondrial depolarization induced by H 2 S was prevented by zinc, methionine and pyruvate all of which decreased H 2 S-induced cell death. Treatment of H 2 S poisoning may benefit from interventions aimed at minimizing ROS-induced damage and reducing mitochondrial damage.
Metabolism, 2000
Hyperhomocysteinemia is a risk factor for vascular disease, although its mechanism of action is not fully clear. Different experimental studies have suggested that homocysteine (Hcy) exerts a pro-oxidant effect in the presence of metal ions (Fe and Cu). To test for a similar effect in vivo, we studied plasma markers of lipid and protein oxidation during hyperhomocysteinemia induced by an oral methionine load. Twenty-nine subjects (aged 61 +/- 25 years; 17 women), 25 of whom underwent oral methionine (100 mg/kg) loading, were studied; in every case, we measured total plasma Hcy, malondialdehyde (MDA), conjugated dienes (DIE), and oxidized protein ([PTOX] carbonylic groups) in basal conditions and 4, 6, 8, and 24 hours after methionine loading. Four participants acted as controls. In every case, we also measured total plasma antioxidant capacity (ANTOX) in basal conditions and 8 hours after methionine loading. Eight hours after methionine loading, plasma Hcy increased from 17.6 +/- 11.4 to 54.3 +/- 31.6 nmol/mL, PTOX from 0.33 +/- 0.18 to 0.71 +/- 0.33 nmol/mg protein, DIE from 493 +/- 163 to 590 +/-202 optical density units, and MDA from 1.66 +/- 0.81 to 2.1 +/- 0.93 nmol/mL. There was a significant correlation (Spearman's r) between Hcy and both PTOX (r = .86, P = .01) and MDA (r = .47, P < .05) 8 hours after methionine loading. No significant modifications of the plasma parameters were found during the observation period in controls. ANTOX at 8 hours was significantly (paired ttest) reduced in probands (from 1.74 +/- 0.59 to 1.14 +/- 0.55 mmol/mL, P = .014); no significant difference was observed for plasma ANTOX in controls. Hyperhomocysteinemia due to oral methionine loading induced an increase in plasma oxidation markers. In the absence of hyperhomocysteinemia, no significant modifications were observed. These findings, together with the decrease in ANTOX and the corresponding increase in total plasma Hcy, are consistent with a pro-oxidant effect of acute hyperhomocysteinemia in vivo.