Reversible Glutathiolation of Caspase-3 by Glutaredoxin as a Novel Redox Signaling Mechanism in Tumor Necrosis Factor-α–Induced Cell Death

Abstract

See related article, pages 213–219 Atherosclerosis and hypertension are cardiovascular diseases that cause distinctive functional and structural changes in the vasculature. These pathological events have been intimately linked to modified cellular behavior in the vessel wall. Cell growth, endothelial apoptosis, smooth muscle migration, inflammation, fibrosis and matrix regulation are all known to contribute to plaque development and hypertension. Reactive oxygen species (ROS) produced by leukocytes, endothelial cells, vascular smooth muscle cells (VSMC), and adventitial fibroblasts play a key role in the initiation and progression of these cellular activities.1,2 ROS have been implicated in numerous physiological and pathological processes depending on their concentrations and kinetic properties. Cells produce ROS such as O2·-, H2O2, and ·OH in response to growth factors, cytokines and shear stress. At relatively low concentrations, ROS produced by these external stimuli play critical roles in redox signaling and normal cell function. However, higher concentrations of ROS induce oxidative damage of DNA, proteins, carbohydrates and lipids.3–5 Cysteine thiol residues on proteins are susceptible to modifications in response to low and high concentrations of ROS and to the cellular redox environment. At relatively low ROS concentrations, cysteine thiols can be modified by glutathiolation (-S-SG) and S-nitrosation (-S-NO). In the presence of increasing ROS concentrations and an oxidative cellular environment, sulfenylation (-S-OH), sulfinylation (-S-O2H) and sulfonylation (-S-O3H) of cysteine residues occur. Of these cysteine modifications, glutathiolation has gained acclaim as an important cellular mechanism. Glutathiolation is the reversible formation of mixed disulfides between protein cysteines and glutathione (GSH). The exact mechanism regulating glutathiolation has not been clearly established, but a recent review by Ghezzi suggests that glutathiolation occurs mainly by thiol-disulfide exchange with GSSG (oxidized GSH).6 This indicates the importance of overall cellular GSH:GSSG ratio …