Regulation of protein function by S-nitrosation and S-glutathionylation: processes and targets in cardiovascular pathophysiology

Abstract

Decades of chemical, biochemical and pathophysiological research have established the relevance of post-translational protein modifications induced by processes related to oxidative stress, with critical reflections on cellular signal transduction pathways. A great deal of the so-called 'redox regulation' of cell function is in fact mediated through reactions promoted by reactive oxygen and nitrogen species on more or less specific aminoacid residues in proteins, at various levels within the cell machinery. Modifications involving cysteine residues have received most attention, due to the critical roles they play in determining the structure/function correlates in proteins. The peculiar reactivity of these residues results in two major classes of modifications, with incorporation of NO moieties (S-nitrosation, leading to formation of protein S-nitrosothiols) or binding of low molecular weight thiols (S-thionylation, i.e . in particular S-glutathionylation, S-cysteinylglycinylation and S-cysteinylation).A wide array of proteins have been thus analyzed in detail as far as their susceptibility to either modification or both, and the resulting functional changes have been described in a number of experimental settings. The present review aims to provide an update of available knowledge in the field, with a special focus on the respective (sometimes competing and antagonistic) roles played by protein S-nitrosations and S-thionylations in biochemical and cellular processes specifically pertaining to pathogenesis of cardiovascular diseases.

Cardiac remodeling and higher sensitivity to ischemia–reperfusion injury in female rats submitted to high-fat high-sucrose diet: An in vivo/ex vivo longitudinal follow-up

“…Finally, ischemia and mostly reflow are well-known to induce high oxidative stress, which is exacerbated here by the 5-month high-fat high-sucrose diet. We also assessed the S-Glutathionylation of proteins, which is the reversible addition of glutathione to cysteine residues inactivating the target proteins [44], and which could be involved in CV complications [45]. Protein S-Glutathionylation occurs mainly at the beginning of reflow in an ischemia-reperfusion protocol and has been shown to be increased in some studies.…”

Mix-and-Match Proteomics: Using Advanced Iodoacetyl Tandem Mass Tag Multiplexing To Investigate Cysteine Oxidation Changes with Respect to Protein Expression

“…The LTQ-Orbitrap Elite acquired a high resolution MS scan (resolving power 60,000 at m/z 400) over a mass range of m/z 380 -1800 in positive mode. A maximum ion injection time of 200 ms was allowed for Orbitrap analyses, with an AGC target of 1x10 6 . The three most abundant multiply charged ions in the MS scan above the set signal thresholds were then selected for consecutive MS/MS analyses by Higher-energy Collisional Dissociation (HCD) and Collision Induced Dissociation (CID).…”

“…3 Cysteine modifications are mediated by changes in redox state and provide a link between oxidative stress and pathologies such as cardiovascular disease, diabetes, neurodegenerative diseases and others. [4][5][6][7][8] Comparative proteomic analyses, which allow protein expression changes to be linked to phenotype, are typically performed under reducing conditions and are thus insensitive to reversible oxidative changes. Several proteomic approaches have been developed to assess differences in cysteine oxidation under conditions of interest (reviewed by Chouchani et al, 2011; Murray & Van Eyk, 2012; Wojdyla & Rogowska-Wrzesinska, 2015).…”

Antioxidant Properties of S-Nitrosoglutathione and Nanotechnologies

“…The S-nitrosation process apart from its ability to modulate signaling pathways by post-translational modification of proteins (Pr-SNO) is also a protection of thiol functions from oxidation [2][3][4]. Indeed, GSNO was shown to be able to reduce disulfide bounds forming S-nitroso functions, which are a lower oxidation state of thiol functions than disulfide or sulfenic/sulfonic acid functions [2,5]. However, the ability of GSNO to regulate NO bioavailability under oxidative stress is poorly studied.…”