Review Article
Redox regulation of electrophilic signaling by reactive persulfides in cardiac cells

https://doi.org/10.1016/j.freeradbiomed.2017.01.024Get rights and content

Highlights

  • Cardiovascular electrophilic signaling is controlled by reactive persulfides.

  • Electrophilic signaling by 8-nitro-cGMP is regulated by reactive persulfides.

  • Long-term exposure to electrophiles may increase the risk for cardiovascular diseases.

  • Reactive persulfides suppress 8-nitro-cGMP-mediated cardiac early senescence.

  • Excessive activation of Nrf2 antioxidant response may cause reductive stress in heart.

Abstract

Maintaining a redox balance by means of precisely controlled systems that regulate production, and elimination, and metabolism of electrophilic substances (electrophiles) is essential for normal cardiovascular function. Electrophilic signaling is mainly regulated by endogenous electrophiles that are generated from reactive oxygen species, nitric oxide, and the derivative reactive species of nitric oxide during stress responses, as well as by exogenous electrophiles including compounds in foods and environmental pollutants. Among electrophiles formed endogenously, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) has unique cell signaling functions, and pathways for its biosynthesis, signaling mechanism, and metabolism in cells have been clarified. Reactive persulfide species such as cysteine persulfides and polysulfides that are endogenously produced in cells are likely to be involved in 8-nitro-cGMP metabolism. These new aspects of redox biology may stimulate innovative and multidisciplinary research in cardiovascular physiology and pathophysiology. In our review, we focus on the redox-dependent regulation of electrophilic signaling via reduction and metabolism of electrophiles by reactive persulfides in cardiac cells, and we include suggestions for a new therapeutic strategy for cardiovascular disease.

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).

References (93)

  • N. Kitajima et al.

    TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts

    Biochem. Biophys. Res. Commun.

    (2011)
  • S. Fujii et al.

    The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response

    J. Biol. Chem.

    (2010)
  • J.A. Doorn et al.

    Covalent adduction of nucleophilic amino acids by 4-hydroxynonenal and 4-oxononenal

    Chem. Biol. Interact.

    (2003)
  • C. Ito et al.

    Endogenous nitrated nucleotide is a key mediator of autophagy and innate defense against bacteria

    Mol. Cell

    (2013)
  • K. Ono et al.

    Redox chemistry and chemical biology of H2S, hydropersulfides, and derived species: implications of their possible biological activity and utility

    Free Radic. Biol. Med.

    (2014)
  • D.P. Jones

    Redox theory of aging

    Redox Biol.

    (2015)
  • M. Nishida

    Roles of heterotrimeric GTP-binding proteins in the progression of heart failure

    J. Pharmacol. Sci.

    (2011)
  • J. Heo et al.

    Mechanism of redox-mediated guanine nucleotide exchange on redox-active Rho GTPases

    J. Biol. Chem.

    (2005)
  • M. Nishida et al.

    Activation mechanism of Gi and Go by reactive oxygen species

    J. Biol. Chem.

    (2002)
  • T.L. Baker et al.

    S-Nitrosocysteine increases palmitate turnover on Ha-Ras in NIH 3T3 cells

    J. Biol. Chem.

    (2000)
  • N. Mishra et al.

    Inhibition of mitochondrial division through covalent modification of Drp1 protein by 15 deoxy-Δ12,14-prostaglandin J2

    Biochem. Biophys. Res. Commun.

    (2010)
  • M. Serrano et al.

    Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a

    Cell

    (1997)
  • P. Korge et al.

    Increased reactive oxygen species production during reductive stress: the roles of mitochondrial glutathione and thioredoxin reductases

    Biochim. Biophys. Acta Bioenerg.

    (2015)
  • M.A. Aon et al.

    Redox-optimized ROS balance: a unifying hypothesis

    Biochim. Biophys. Acta

    (2010)
  • S. Cortassa et al.

    Redox-optimized ROS balance and the relationship between mitochondrial respiration and ROS

    Biochim. Biophys. Acta

    (2014)
  • F. Singh et al.

    Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis

    Biochim. Biophys. Acta

    (2015)
  • K. Itoh et al.

    An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements

    Biochem. Biophys. Res. Commun.

    (1997)
  • Y. Zhang et al.

    4-Hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway

    J. Mol. Cell. Cardiol.

    (2010)
  • T. Finkel

    Signal transduction by reactive oxygen species

    J. Cell Biol.

    (2011)
  • J.R. Lancaster

    Nitroxidative, nitrosative, and nitrative stress: kinetic predictions of reactive nitrogen species chemistry under biological conditions

    Chem. Res. Toxicol.

    (2006)
  • Y. Saito et al.

    Angiotensin II-mediated signal transduction pathways

    Curr. Hypertens. Rep.

    (2002)
  • R.M. Touyz

    Reactive oxygen species as mediators of calcium signaling by angiotensin II: implications in vascular physiology and pathophysiology

    Antioxid. Redox Signal.

    (2005)
  • M. Nishida et al.

    Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration

    Nat. Chem. Biol.

    (2012)
  • M. Ristow et al.

    Antioxidants prevent health-promoting effects of physical exercise in humans

    Proc. Natl. Acad. Sci. USA

    (2009)
  • C.G. Sharoff et al.

    Combining short-term metformin treatment and one bout of exercise does not increase insulin action in insulin-resistant individuals

    Am. J. Physiol. Endocrinol. Metab.

    (2010)
  • A.C. Brewer et al.

    Reductive stress linked to small HSPs, G6PD, and Nrf2 pathways in heart disease

    Antioxid. Redox Signal.

    (2013)
  • O.N. Ursu et al.

    Heme oxygenase-1 mediates oxidative stress and apoptosis in coxsackievirus B3-induced myocarditis

    Cell. Physiol. Biochem.

    (2014)
  • J.D. Lambeth

    NOX enzymes and the biology of reactive oxygen

    Nat. Rev. Immunol.

    (2004)
  • J.R. Burgoyne et al.

    Hydrogen peroxide sensing and signaling by protein kinases in the cardiovascular system

    Antioxid. Redox Signal.

    (2013)
  • A.P. West et al.

    TLR signalling augments macrophage bactericidal activity through mitochondrial ROS

    Nature

    (2011)
  • J.C. McCann et al.

    Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging

    FASEB J.

    (2011)
  • M. de Lorgeril et al.

    Selenium and antioxidant defenses as major mediators in the development of chronic heart failure

    Heart Fail. Rev.

    (2006)
  • Y. Zhang et al.

    Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity

    J. Gerontol. Biol. Sci. Med. Sci.

    (2009)
  • A. Tosaki et al.

    The role of peroxiredoxins in ischemia-reperfusion-induced cardiac damage

    Am. J. Physiol. Heart Circ. Physiol.

    (2006)
  • H. Sumimoto

    Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species

    FEBS J.

    (2008)
  • S. Matsushima et al.

    Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

    J. Clin. Investig.

    (2016)
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