Effects of glutathione reductase inhibition on cellular thiol redox state and related systems

Zhao, Yong; Seefeldt, Teresa; Chen, Wei; Wang, Xiuqing; Matthees, Duane P.; Hu, Yueshan; Guan, Xiaoxu

doi:10.1016/j.abb.2009.03.001

Cited by 61 publications

(52 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GSH is an important antioxidant agent that protects the cells from oxidative stress (31). After VSMCs were treated with MG for 24 h, cellular GSH level was significantly increased correspondingly to the concentrations of MG (10-50 mM) (Fig.…”

Section: Gsh Cysteine and Homocysteine Levels In Mg-or Nahs-treatedmentioning

confidence: 94%

See 1 more Smart Citation

Interaction of Methylglyoxal and Hydrogen Sulfide in Rat Vascular Smooth Muscle Cells

Chang

Untereiner

Liu

et al. 2010

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Hydrogen sulfide (H(2)S) is a gasotransmitter with multifaceted physiological functions, including the regulation of glucose metabolism. Methylglyoxal (MG) is an intermediate of glucose metabolism and plays an important role in the pathogenesis of insulin resistance syndromes. In the present study, we investigated the effect of MG on H(2)S synthesis and the interaction between these two endogenous substances. In cultured vascular smooth muscle cells (VSMCs), MG (10, 30, and 50 microM) significantly decreased cellular H(2)S levels in a concentration-dependent manner, while H(2)S donor, NaHS (30, 60, and 90 microM), significantly decreased cellular MG levels. The expression level and activity of H(2)S-producing enzyme, cystathionine gamma-lyase (CSE), were significantly decreased by MG treatment. NaHS (30-90 microM) significantly inhibited MG (10 or 30 microM)-induced ROS production. Cellular levels of GSH, cysteine, and homocysteine were also increased by MG or NaHS treatment. Furthermore, direct reaction of H(2)S with MG in both concentration- and time-dependent manners were observed in in vitro incubations. In conclusion, MG regulates H(2)S level in VSMCs by downregulating CSE protein expression and directly reacting with H(2)S molecule. Interaction of MG with H(2)S may be one of future directions for the studies on glucose metabolism and the development of insulin resistance syndromes.

show abstract

Section: Gsh Cysteine and Homocysteine Levels In Mg-or Nahs-treatedmentioning

confidence: 94%

“…cells (31). GSH levels are significantly elevated when the cells are treated with MG (10, 30, and 50 mM) compared to that of the control group.…”

mentioning

confidence: 95%

Interaction of Methylglyoxal and Hydrogen Sulfide in Rat Vascular Smooth Muscle Cells

Chang

Untereiner

Liu

et al. 2010

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…In neurons, the decrease in ATP levels could be due to a reduction in NADH generation in mitochondria caused by the damage to KGDHC and aconitase and/or some other unidentified catabolic enzymes. In addition, the elevation of NADPH could have been caused by an increased production via Pentose Phosphate Pathway (30) and/or by an inhibition of Glutathione Reductase (GR) (70). Indeed, it has been reported that the low glycolytic rate in neurons results in increased flux through the pentosephosphate pathway, thus providing NADPH necessary to regenerate antioxidant glutathione (30).…”

mentioning

confidence: 99%

Oxidative Damage Compromises Energy Metabolism in the Axonal Degeneration Mouse Model of X-Adrenoleukodystrophy

Galino

Ruíz

Fourcade

et al. 2011

Antioxidants & Redox Signaling

105

View full text Add to dashboard Cite

Aims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, we have chosen the mouse model of adrenoleukodystrophy (X-ALD), which exhibits axonal degeneration in spinal cords and motor disability. The disease is caused by loss of function of the ABCD1 transporter, involved in the import and degradation of very long-chain fatty acids (VLCFA) in peroxisomes. Oxidative stress due to VLCFA excess appears early in the neurodegenerative cascade. Results: In this study, we demonstrate by redox proteomics that oxidative damage to proteins specifically affects five key enzymes of glycolysis and TCA (Tricarboxylic acid) cycle in spinal cords of Abcd1 -mice and pyruvate kinase in human X-ALD fibroblasts. We also show that NADH and ATP levels are significantly diminished in these samples, together with decrease of pyruvate kinase activities and GSH levels, and increase of NADPH. Innovation: Treating Abcd1 -mice with the antioxidants N-acetylcysteine and a-lipoic acid (LA) prevents protein oxidation; preserves NADH, NADPH, ATP, and GSH levels; and normalizes pyruvate kinase activity, which implies that oxidative stress provoked by VLCFA results in bioenergetic dysfunction, at a presymptomatic stage. Conclusion: Our results provide mechanistic insight into the beneficial effects of antioxidants and enhance the rationale for translation into clinical trials for X-adrenoleukodystrophy. Antioxid. Redox Signal. 15, 2095Signal. 15, -2107

show abstract

“…1A). Similarly, an inhibitor of glutathione reductase, 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanyl thiocarbonylamino) phenylthiocarbamoylsulfanyl] propionic acid (2-AAPA), which increases GSH-protein adducts (14), increased HIF-1α protein levels (Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization

Watanabe

Murdoch

Sano

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Reactive oxygen species (ROS) are increased in ischemic tissues and necessary for revascularization; however, the mechanism remains unclear. Exposure of cysteine residues to ROS in the presence of glutathione (GSH) generates GSH-protein adducts that are specifically reversed by the cytosolic thioltransferase, glutaredoxin-1 (Glrx). Here, we show that a key angiogenic transcriptional factor hypoxiainducible factor (HIF)-1α is stabilized by GSH adducts, and the genetic deletion of Glrx improves ischemic revascularization. In mouse muscle C2C12 cells, HIF-1α protein levels are increased by increasing GSH adducts with cell-permeable oxidized GSH (GSSG-ethyl ester) or 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanyl thiocarbonylamino) phenylthiocarbamoylsulfanyl] propionic acid (2-AAPA), an inhibitor of glutathione reductase. A biotin switch assay shows that GSSG-ester-induced HIF-1α contains reversibly modified thiols, and MS confirms GSH adducts on Cys 520 (mouse Cys 533 ). In addition, an HIF-1α Cys 520 serine mutant is resistant to 2-AAPA-induced HIF-1α stabilization. Furthermore, Glrx overexpression prevents HIF-1α stabilization, whereas Glrx ablation by siRNA increases HIF-1α protein and expression of downstream angiogenic genes. Blood flow recovery after femoral artery ligation is significantly improved in Glrx KO mice, associated with increased levels of GSH-protein adducts, capillary density, vascular endothelial growth factor (VEGF)-A, and HIF-1α in the ischemic muscles. Therefore, Glrx ablation stabilizes HIF-1α by increasing GSH adducts on Cys 520 promoting in vivo HIF-1α stabilization, VEGF-A production, and revascularization in the ischemic muscles.GSH-protein adducts | S-glutathionylation | hypoxia-inducible factor-1 | glutaredoxin-1 | ischemic limb revascularization D espite the notion that increased oxidants are deleterious, clinical trials of antioxidant therapies failed to prevent cardiovascular diseases (1). In mouse models, decreasing reactive oxygen species (ROS) impaired ischemic revascularization after hind limb ischemia (2, 3), and in contrast, increased ROS (4) or decreased antioxidants (5) improved ischemic revascularization. Therefore, ROS play a protective role in ischemic revascularization. However, little is known about the molecular mechanism by which ROS improve ischemic revascularization.It is generally recognized that ROS change protein function by posttranslational modifications of cysteine thiols (-SH) (6). Protein thiols are susceptible to oxidation and give rise to reversible oxidative modifications including S-sulfenylation (-SOH), S-nitrosylation (-SNO), and glutathione (GSH)-protein adducts [S-glutathionylation (-SSG)] (7). These reversible modifications can regulate cellular signaling and may contribute to ROS-induced ischemic revascularization. Interestingly, S-nitrosylation has been indicated as a mechanism of nitric oxide (NO)-mediated signaling and shown to stabilize hypoxia-inducible factor (HIF)-1α, a master angiogenic transcriptional regulator (8).S-nitrosyl...

show abstract

Effects of glutathione reductase inhibition on cellular thiol redox state and related systems

Cited by 61 publications

References 36 publications

Interaction of Methylglyoxal and Hydrogen Sulfide in Rat Vascular Smooth Muscle Cells

Interaction of Methylglyoxal and Hydrogen Sulfide in Rat Vascular Smooth Muscle Cells

Oxidative Damage Compromises Energy Metabolism in the Axonal Degeneration Mouse Model of X-Adrenoleukodystrophy

Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization

Contact Info

Product

Resources

About