Review ArticleRedox regulation of electrophilic signaling by reactive persulfides in cardiac cells
Graphical abstract
Introduction
Reduction/oxidation (redox) signaling caused by modulation of redox homeostasis has long been widely regarded as a major risk factor for cardiac disease. Endogenous redox balance is maintained by means of tightly controlled systems that regulate production and scavenging of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [1], [2]. Oxidative stress caused by the accumulation of ROS and RNS induced by neurohumoral factors and/or hemodynamic pressure load mediates the development of cardiovascular remodeling through post-translational modification of intracellular signaling proteins [3], [4]. We discovered that irreversible cysteine modification by electrophilic byproducts, such as nitrated cyclic nucleotides (e.g. 8-nitroguanosine 3',5'-cyclic monophosphate [8-nitro-cGMP]), which have been generated in reactions of ROS, RNS, and intracellular guanine nucleotides, functions as a key mediator of chronic heart failure [5]. Several studies with gene-targeted mice, however, have revealed that ROS and RNS function as essential signaling mediators rather than cytotoxic factors in maintaining physiological functions. Notably, physical exercise, by generating large amounts of ROS, supposedly creates the oxidative redox potential required for oxidizing free sulfhydryl groups of cysteine and producing the disulfide bonds used to stabilize the three-dimensional conformation of physiologically active proteins [6]. Antioxidant supplements reportedly prevent the health-promoting effects of physical exercise in humans [7], and short-term treatment with metformin, an antidiabetic drug, cancels the effect of physical exercise by enhancing insulin sensitivity as a result of attenuating the oxidative effects of physical exercise [8], [9]. Thus, type 2 diabetes is now considered to be a redox disease, and appropriate ROS production is physiologically essential to maintain the redox balance as well as cardiovascular homeostasis. This concept is supported by the surprising discovery that the counterpart of oxidative stress, i.e. reductive stress, contributes to the cardiomyopathy that is caused by protein aggregation [10], [11], [12], [13]. Reductive stress results from an increase in reduced glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH), and heme oxygenase-1 (HO-1), which is related to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), an oxidative stress-responsive transcriptional factor [10], [11], [12], [13]. The traditional concept of oxidative stress is that the toxic effects of ROS are protected by diverse antioxidant systems that are up-regulated by oxidative stress responses that are physiologically mediated by redox-dependent cell signaling pathways. In other words, both oxidative stress and reductive stress should work together closely in increasing the risk of cardiovascular diseases. This finding indicates that maintaining a redox balance may be a novel therapeutic strategy for preventing and treating cardiovascular disease rather than simply reducing oxidative stress.
Section snippets
Spatiotemporal regulation of ROS signaling in the heart
ROS-dependent signaling pathways activated by physicochemical stimuli are mainly mediated by two major ROS-producing pathways: enzymatic functions of NADPH oxidases (Noxs) and the mitochondrial electron transport chain. Alternative enzymes, such as xanthine oxidase, aldehyde oxidase, cytochrome P450, urate oxidase, d-amino oxidases, and uncoupled nitric oxide (NO) synthases may also participate in the ROS-dependent signaling process [14], [15], [16]. Each enzyme reportedly forms an original
G proteins as essential mediators of cardiac remodeling
Structural and morphological changes of the heart (cardiac remodeling), caused by one or more risk factors such as high blood pressure, hyperglycemia, being overweight or obese, and smoking, are major clinical outcomes of heart failure. Several neurohumoral factors, such as angiotensin II, endothelin-1, and norepinephrine and their corresponding G protein-coupled receptors, reportedly mediated the development of cardiac remodeling [54]. G proteins serve as binary molecular switches and regulate
Reductive stress in protein aggregation cardiomyopathy
Oxidative stress, which is characterized by a shift in the oxidative/reductive potential to a more oxidative state because of excess production of ROS and RNS and/or electrophiles, acts as a mediator of physiological aging and wound healing or of pathophysiological events such as atherosclerosis, hypertension, heart failure, and ischemia-reperfusion injury. Conversely, reductive stress, which is characterized by a shift in the redox balance from an oxidative to a reduced state because of an
Conclusions
By using 8-nitro-cGMP as a moderate electrophilic ligand, we showed that endogenously formed reactive persulfide species, such as reactive cysteine persulfides found in abundant amounts in cells, possess highly antioxidant and nucleophilic properties that prevent 8-nitro-cGMP-mediated senescent signaling in rodent hearts. These reactive persulfide species are also critically involved in detoxification of environmental electrophiles, which suggests that the redox balance between the background
Funding sources
This work was supported in part by Grants-in-Aid for Scientific Research (16KT0013 to M.N. and T.A.; 15K18883 to A.N.; and 25253020 to T.A.), and Grants-in-Aid for Scientific Research on Innovative Areas (Research in a Proposed Research Area) (26111008, 26111001 to T.A.), from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). This work was also supported by PRESTO, Japan Science and Technology Agency (JST).
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