Regulation of Cell Physiology and Pathology by Protein S-Glutathionylation: Lessons Learned from the Cardiovascular System

Abstract

Significance: Reactive oxygen and nitrogen species contributing to homeostatic regulation and the pathogenesis of various cardiovascular diseases, including atherosclerosis, hypertension, endothelial dysfunction, and cardiac hypertrophy, is well established. The ability of oxidant species to mediate such effects is in part dependent on their ability to induce specific modifications on particular amino acids, which alter protein function leading to changes in cell signaling and function. The thiol containing amino acids, methionine and cysteine, are the only oxidized amino acids that undergo reduction by cellular enzymes and are, therefore, prime candidates in regulating physiological signaling. Various reports illustrate the significance of reversible oxidative modifications on cysteine thiols and their importance in modulating cardiovascular function and physiology. Recent Advances: The use of mass spectrometry, novel labeling techniques, and live cell imaging illustrate the emerging importance of reversible thiol modifications in cellular redox signaling and have advanced our analytical abilities. Critical Issues: Distinguishing redox signaling from oxidative stress remains unclear. S-nitrosylation as a precursor of S-glutathionylation is controversial and needs further clarification. Subcellular distribution of glutathione (GSH) may play an important role in local regulation, and targeted tools need to be developed. Furthermore, cellular redundancies of thiol metabolism complicate analysis and interpretation. Future Directions: The development of novel pharmacological analogs that specifically target subcellular compartments of GSH to promote or prevent local protein S-glutathionylation as well as the establishment of conditional gene ablation and transgenic animal models are needed. Antioxid. Redox Signal. 16, 524-542.

Posttranslational Modification of Cysteine in Redox Signaling and Oxidative Stress: Focus on S-Glutathionylation

“…Thus, antibodies directed against specific glutathionylated peptides of key regulatory proteins would facilitate in situ analysis of specific signaling intermediates, and specific glutathionylated peptides could be used as internal standards for quantitative mass spectrometric analyses of changes in protein-SSG under different physiological or pathophysiological conditions. For other perspectives and more critical discussion of current methods, see this Forum (21,30), as well as previous reviews (1,7,10,22,25).…”

Carbon Monoxide Signaling in Human Red Blood Cells: Evidence for Pentose Phosphate Pathway Activation and Protein Deglutathionylation

“…Importantly, glutathionylation can be reversed in a reducing environment, in an enzyme-dependent or independent manner (7,13,15,36,58). Notably, a previous report (9) showed that RBC protein glutathionylation (mainly Hb) in human blood decreased immediately after the oxidative challenge and increased again in parallel with the modification of the GSH-GSSG ratio.…”

“…The indication that Hb deglutathionylation was a likely mechanism explaining the CO-mediated GSH increase in RBCs led us to investigate the involvement of enzymes known to favor this reaction such as GR, glutaredoxin (25), Trx/TrxR, or sulfiredoxin (Srx) (13,25,32,36) (Fig. 8A).…”

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

“…Recent studies suggest that the NO-mediated pathway and the ROS-mediated pathway may have extensive crosstalk (37,93,132); the reaction between NO and superoxide gives rise to peroxynitrite, which can be a potent mediator of S-glutathionylation in the presence of GSH; NO may form protein-SNO, which can serve as a precursor to protein-SSG. And in the case of RyR channels, S-nitrosylation and S-glutathionylation may compete for the same cysteine residues (4).…”

“…Oxidative stress, or reactive oxygen species (ROS), facilitates S-glutathionylation. Protein S-glutathionylation has been extensively discussed in many excellent reviews with a variety of different emphases (31,44,45,75,76,88,93,100,107). Over the past few years, S-glutathionylation has been increasingly observed in many ion channels, such as voltage-gated calcium channels, ryanodine receptor (RyR), and ATP-sensitive potassium channels (K ATP channels), all of which contribute to critical cellular functions (4,123,137,138).…”