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1.  Functional Analysis of Novel Analogues of E3330 That Block the Redox Signaling Activity of the Multifunctional AP Endonuclease/Redox Signaling Enzyme APE1/Ref-1 
Antioxidants & Redox Signaling  2011;14(8):1387-1401.
Abstract
APE1 is a multifunctional protein possessing DNA repair and redox activation of transcription factors. Blocking these functions leads to apoptosis, antiangiogenesis, cell-growth inhibition, and other effects, depending on which function is blocked. Because a selective inhibitor of the APE redox function has potential as a novel anticancer therapeutic, new analogues of E3330 were synthesized. Mass spectrometry was used to characterize the interactions of the analogues (RN8-51, 10-52, and 7-60) with APE1. RN10-52 and RN7-60 were found to react rapidly with APE1, forming covalent adducts, whereas RN8-51 reacted reversibly. Median inhibitory concentration (IC50 values of all three compounds were significantly lower than that of E3330. EMSA, transactivation assays, and endothelial tube growth-inhibition analysis demonstrated the specificity of E3330 and its analogues in blocking the APE1 redox function and demonstrated that the analogues had up to a sixfold greater effect than did E3330. Studies using cancer cell lines demonstrated that E3330 and one analogue, RN8-51, decreased the cell line growth with little apoptosis, whereas the third, RN7-60, caused a dramatic effect. RN8-51 shows particular promise for further anticancer therapeutic development. This progress in synthesizing and isolating biologically active novel E3330 analogues that effectively inhibit the APE1 redox function validates the utility of further translational anticancer therapeutic development. Antioxid. Redox Signal. 14, 1387–1401.
doi:10.1089/ars.2010.3410
PMCID: PMC3061197  PMID: 20874257
2.  Redox signaling, vascular function and hypertension 
Antioxidants & redox signaling  2008;10(6):1045-1059.
Accumulating evidence supports the importance of redox signaling in the pathogenesis and progression of hypertension. Redox signaling is implicated in many different physiological and pathological processes in the vasculature. High blood pressure is in part determined by elevated total peripheral vascular resistance, which is ascribed to dysregulation of vasomotor function and structural remodeling of blood vessels. Aberrant redox signaling, usually induced by excessive production of reactive oxygen species (ROS) and/or by decreases in antioxidant activity, can induce alteration of vascular function. ROS increase vascular tone by influencing the regulatory role of endothelium and by direct effects on the contractility of vascular smooth muscle. ROS contribute to vascular remodeling by influencing phenotype modulation of vascular smooth muscle cells, aberrant growth and death of vascular cells, cell migration, and extracellular matrix (ECM) reorganization. Thus, there are diverse roles of the vascular redox system in hypertension, suggesting that the complexity of redox signaling in distinct spatial spectrums should be considered for a better understanding of hypertension.
doi:10.1089/ars.2007.1986
PMCID: PMC2828811  PMID: 18321201
3.  Lipid Raft Redox Signaling: Molecular Mechanisms in Health and Disease 
Antioxidants & Redox Signaling  2011;15(4):1043-1083.
Abstract
Lipid rafts, the sphingolipid and cholesterol-enriched membrane microdomains, are able to form different membrane macrodomains or platforms upon stimulations, including redox signaling platforms, which serve as a critical signaling mechanism to mediate or regulate cellular activities or functions. In particular, this raft platform formation provides an important driving force for the assembling of NADPH oxidase subunits and the recruitment of other related receptors, effectors, and regulatory components, resulting, in turn, in the activation of NADPH oxidase and downstream redox regulation of cell functions. This comprehensive review attempts to summarize all basic and advanced information about the formation, regulation, and functions of lipid raft redox signaling platforms as well as their physiological and pathophysiological relevance. Several molecular mechanisms involving the formation of lipid raft redox signaling platforms and the related therapeutic strategies targeting them are discussed. It is hoped that all information and thoughts included in this review could provide more comprehensive insights into the understanding of lipid raft redox signaling, in particular, of their molecular mechanisms, spatial-temporal regulations, and physiological, pathophysiological relevances to human health and diseases. Antioxid. Redox Signal. 15, 1043–1083.
I. Introduction
II. Redox Signaling and Redox Injury
A. Redox signaling
B. Redox signaling versus injury
C. Common ROS as messengers
III. Concepts of LRs and Their Clustering
A. Concepts of LRs and existing debates
B. Molecular models of LRs
C. LRs on cell membranes
1. Caveolar LRs
2. Noncaveolar LRs
3. Ceramide-enriched micro- and macrodomains
D. Intracellular LRs
E. LR clusters or signaling platforms
IV. Redox Molecules Associated with LRs
A. The NADPH oxidase family
1. Structure of the NADHP oxidase family and their tissue distribution
2. Assembly and activation of NOX
3. Regulation of NOX activity
B. Superoxide dismutase
C. Catalase
D. Thioredoxin
E. Transient receptor protein C3 and C4: redox sensors
F. Effects of redox molecules on LRs
V. Frequently Used Methods for Identifying LR Redox Signaling Platforms
A. Fluorescent confocal microscopic imaging
B. Fluorescence resonance energy transfer
C. Membrane fraction flotation
D. Superoxide production in LR platforms
E. Others
VI. Downstream Targets of LR Redox Signaling
A. Signaling in phagocytic process
B. Transmembrane signaling via receptors in nonphagocytic cells
C. LR redox signaling not via receptors
D. Interactions of intracellular vesicles or organelles through LR redox signaling
E. Hypothetic models of LR redox signaling platforms
VII. Mechanisms Mediating the Formation of LR Redox Signaling Platforms
A. Ceramide metabolizing pathways
B. Association of ceramide metabolism and its signaling pathway
C. Role of ceramide-enriched microdomains in LRs clustering
D. Lysosome fusion and targeting of ASMase in LRs clustering
E. Cytoskeletal components and LR clustering
F. Feedforward amplifying mechanism
VIII. Physiology and Pathophysiology of LR Redox Signaling Platforms
A. Host defense and infection
B. Vascular inflammation and atherosclerosis
C. AD and neurological disease
D. Kidney diseases
E. Obesity
F. Tumors
IX. Possible Therapeutic Strategies Targeting LR Redox Signaling Platforms
A. Targeting cholesterol
B. Targeting ASMase activity
C. Targeting protein palmitoylation
X. Conclusions and Perspectives
doi:10.1089/ars.2010.3619
PMCID: PMC3135227  PMID: 21294649
4.  Redox Signaling, Vascular Function, and Hypertension 
Antioxidants & Redox Signaling  2008;10(6):1045-1059.
Abstract
Accumulating evidence supports the importance of redox signaling in the pathogenesis and progression of hypertension. Redox signaling is implicated in many different physiological and pathological processes in the vasculature. High blood pressure is in part determined by elevated total peripheral vascular resistance, which is ascribed to dysregulation of vasomotor function and structural remodeling of blood vessels. Aberrant redox signaling, usually induced by excessive production of reactive oxygen species (ROS) and/or by decreases in antioxidant activity, can induce alteration of vascular function. ROS increase vascular tone by influencing the regulatory role of endothelium and by direct effects on the contractility of vascular smooth muscle. ROS contribute to vascular remodeling by influencing phenotype modulation of vascular smooth muscle cells, aberrant growth and death of vascular cells, cell migration, and extracellular matrix (ECM) reorganization. Thus, there are diverse roles of the vascular redox system in hypertension, suggesting that the complexity of redox signaling in distinct spatial spectrums should be considered for a better understanding of hypertension. Antioxid. Redox Signal. 10, 1045–1059.
doi:10.1089/ars.2007.1986
PMCID: PMC2828811  PMID: 18321201
5.  Thiol-Redox Signaling, Dopaminergic Cell Death, and Parkinson's Disease 
Antioxidants & Redox Signaling  2012;17(12):1764-1784.
Abstract
Significance: Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta, which has been widely associated with oxidative stress. However, the mechanisms by which redox signaling regulates cell death progression remain elusive. Recent Advances: Early studies demonstrated that depletion of glutathione (GSH), the most abundant low-molecular-weight thiol and major antioxidant defense in cells, is one of the earliest biochemical events associated with PD, prompting researchers to determine the role of oxidative stress in dopaminergic cell death. Since then, the concept of oxidative stress has evolved into redox signaling, and its complexity is highlighted by the discovery of a variety of thiol-based redox-dependent processes regulating not only oxidative damage, but also the activation of a myriad of signaling/enzymatic mechanisms. Critical Issues: GSH and GSH-based antioxidant systems are important regulators of neurodegeneration associated with PD. In addition, thiol-based redox systems, such as peroxiredoxins, thioredoxins, metallothioneins, methionine sulfoxide reductases, transcription factors, as well as oxidative modifications in protein thiols (cysteines), including cysteine hydroxylation, glutathionylation, and nitrosylation, have been demonstrated to regulate dopaminergic cell loss. Future Directions: In this review, we summarize major advances in the understanding of the role of thiol-redox signaling in dopaminergic cell death in experimental PD. Future research is still required to clearly understand how integrated thiol-redox signaling regulates the activation of the cell death machinery, and the knowledge generated should open new avenues for the design of novel therapeutic approaches against PD. Antioxid. Redox Signal. 17, 1764–1784.
doi:10.1089/ars.2011.4501
PMCID: PMC3474187  PMID: 22369136
6.  Lipid rafts and caveolae and their role in compartmentation of redox signaling 
Antioxidants & redox signaling  2009;11(6):1357-1372.
Membrane (lipid) rafts and caveolae, a subset of rafts, are cellular domains that concentrate plasma membrane proteins and lipids involved in the regulation of cell function. In addition to providing signaling platforms for G-protein-coupled receptors and certain tyrosine kinase receptors, rafts/caveolae can influence redox signaling. This review discusses molecular characteristics of and methods to study rafts/caveolae, determinants that contribute to the localization of molecules in these entities, an overview of signaling molecules that show such localization, and the contribution of rafts/caveolae to redox signaling. Of particular note is the evidence that endothelial nitric oxide synthase (eNOS), NADPH oxygenase and heme oxygenase, along with other less well-studied redox systems, localize in rafts and caveolae. The precise basis for this localization and the contribution of raft/caveolae-localized redox components to physiology and disease are important issues for future studies.
doi:10.1089/ARS.2008.2365
PMCID: PMC2757136  PMID: 19061440
7.  Lipid Rafts and Caveolae and Their Role in Compartmentation of Redox Signaling 
Antioxidants & Redox Signaling  2009;11(6):1357-1372.
Abstract
Membrane (lipid) rafts and caveolae, a subset of rafts, are cellular domains that concentrate plasma membrane proteins and lipids involved in the regulation of cell function. In addition to providing signaling platforms for G-protein-coupled receptors and certain tyrosine kinase receptors, rafts/caveolae can influence redox signaling. This review discusses molecular characteristics of and methods to study rafts/caveolae, determinants that contribute to the localization of molecules in these entities, an overview of signaling molecules that show such localization, and the contribution of rafts/caveolae to redox signaling. Of particular note is the evidence that endothelial nitric oxide synthase (eNOS), NADPH oxygenase, and heme oxygenase, along with other less well-studied redox systems, localize in rafts and caveolae. The precise basis for this localization and the contribution of raft/caveolae-localized redox components to physiology and disease are important issues for future studies. Antioxid. Redox Signal. 11, 1357–1372.
doi:10.1089/ars.2008.2365
PMCID: PMC2757136  PMID: 19061440
8.  Compartmentalization of Redox Signaling Through NADPH Oxidase–Derived ROS 
Antioxidants & Redox Signaling  2009;11(6):1289-1299.
Abstract
Reactive oxygen species (ROS) are generated in response to growth factors, cytokines, G protein–coupled receptor agonists, or shear stress, and function as signaling molecules in nonphagocytes. However, it is poorly understood how freely diffusible ROS can activate specific signaling, so-called “redox signaling.” NADPH oxidases are a major source of ROS and now recognized to have specific subcellular localizations, and this targeting to specific compartments is required for localized ROS production. One important mechanism may involve the interaction of oxidase subunits with various targeting proteins localized in lamellipodial leading edge and focal adhesions/complexes. ROS are believed to inactivate protein tyrosine phosphatases, thereby establishing a positive-feedback system that promotes activation of specific redox signaling pathways involved in various functions. Additionally, ROS production may be localized through interactions of NADPH oxidase with signaling platforms associated with caveolae/lipid rafts, endosomes, and nucleus. These indicate that the specificity of ROS-mediated signal transduction may be modulated by the localization of Nox isoforms and their regulatory subunits within specific subcellular compartments. This review summarizes the recent progress on compartmentalization of redox signaling via activation of NADPH oxidase, which is implicated in cell biology and pathophysiologies. Antioxid. Redox Signal. 11, 1289–1299.
doi:10.1089/ars.2008.2333
PMCID: PMC2842113  PMID: 18999986
9.  Mitochondria and Redox Signaling in Steatohepatitis 
Antioxidants & Redox Signaling  2011;15(2):485-504.
Abstract
Alcoholic and nonalcoholic fatty liver diseases are potentially pathological conditions that can progress to steatohepatitis, fibrosis, and cirrhosis. These conditions affect millions of people throughout the world in part through poor lifestyle choices of excess alcohol consumption, overnutrition, and lack of regular physical activity. Abnormal mitochondrial and cellular redox homeostasis has been documented in steatohepatitis and results in alterations of multiple redox-sensitive signaling cascades. Ultimately, these changes in signaling lead to altered enzyme function and transcriptional activities of proteins critical to mitochondrial and cellular function. In this article, we review the current hypotheses linking mitochondrial redox state to the overall pathophysiology of alcoholic and nonalcoholic steatohepatitis and briefly discuss the current therapeutic options under investigation. Antioxid. Redox Signal. 15, 485–504.
doi:10.1089/ars.2010.3795
PMCID: PMC3118705  PMID: 21128703
10.  ERRATUM: Author-Reported Correction of Western Blot Data: Kim JH, Park B, Gupta SC, Kannappan R, Sung B, and Aggarwal BB. Antioxid Redox Signal 16:413–427, 2012 
Antioxidants & Redox Signaling  2013;18(2):219-220.
Abstract
This is a non-peer-reviewed author-reported erratum addressing that Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through upregulation of death receptors and downregulation of survival proteins: role of reactive oxygen species-dependent CCAAT/enhancer-binding protein–homologous protein pathway. Kim JH, Park B, Gupta SC, Kannappan R, Sung B, and Aggarwal BB. Antioxid Redox Signal 16:413–427, 2012. The authors claim that Figure 7 reporting Western blot data was erroneous. Specifically, the β-actin panel of Fig. 7B was found to be switched with that of Fig. 7D. The corrected version is reported here. The authors claim that this correction does not influence the conclusion of the study.
doi:10.1089/ars.2012.4968
PMCID: PMC3513985
11.  Posttranslational Modification of Cysteine in Redox Signaling and Oxidative Stress: Focus on S-Glutathionylation 
Antioxidants & Redox Signaling  2012;16(6):471-475.
Abstract
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have become recognized as second messengers for initiating and/or regulating vital cellular signaling pathways, and they are known also as deleterious mediators of cellular stress and cell death. ROS and RNS, and their cross products like peroxynitrite, react primarily with cysteine residues whose oxidative modification leads to functional alterations in the proteins. In this Forum, the collection of six review articles presents a perspective on the broad biological impact of cysteine modifications in health and disease from the molecular to the cellular and organismal levels, focusing in particular on reversible protein-S-glutathionylation and its central role in transducing redox signals as well as protecting proteins from irreversible cysteine oxidation. The Forum review articles consider the role of S-glutationylation in regulation of the peroxiredoxin enzymes, the special redox environment of the mitochondria, redox regulation pertinent to the function of the cardiovascular system, mechanisms of redox-activated apoptosis in the pulmonary system, and the role of glutathionylation in the initiation, propagation, and treatment of neurodegenerative diseases. Several common themes emerge from these reviews; notably, the probability of crosstalk between signaling/regulation mechanisms involving protein-S-nitrosylation and protein-S-glutathionylation, and the need for quantitative analysis of the relationship between specific cysteine modifications and corresponding functional changes in various cellular contexts. Antioxid. Redox Signal. 16, 471–475.
doi:10.1089/ars.2011.4454
PMCID: PMC3270050  PMID: 22136616
12.  Antioxidants, Redox Signaling, and Pathophysiology in Schizophrenia: An Integrative View 
Antioxidants & Redox Signaling  2011;15(7):2011-2035.
Abstract
Schizophrenia (SZ) is a brain disorder that has been intensively studied for over a century; yet, its etiology and multifactorial pathophysiology remain a puzzle. However, significant advances have been made in identifying numerous abnormalities in key biochemical systems. One among these is the antioxidant defense system (AODS) and redox signaling. This review summarizes the findings to date in human studies. The evidence can be broadly clustered into three major themes: perturbations in AODS, relationships between AODS alterations and other systems (i.e., membrane structure, immune function, and neurotransmission), and clinical implications. These domains of AODS have been examined in samples from both the central nervous system and peripheral tissues. Findings in patients with SZ include decreased nonenzymatic antioxidants, increased lipid peroxides and nitric oxides, and homeostatic imbalance of purine catabolism. Reductions of plasma antioxidant capacity are seen in patients with chronic illness as well as early in the course of SZ. Notably, these data indicate that many AODS alterations are independent of treatment effects. Moreover, there is burgeoning evidence indicating a link among oxidative stress, membrane defects, immune dysfunction, and multineurotransmitter pathologies in SZ. Finally, the body of evidence reviewed herein provides a theoretical rationale for the development of novel treatment approaches. Antioxid. Redox Signal. 15, 2011–2035.
doi:10.1089/ars.2010.3603
PMCID: PMC3159108  PMID: 21126177
13.  Redox Signaling and the Innate Immune System in Alcoholic Liver Disease 
Antioxidants & Redox Signaling  2011;15(2):523-534.
Abstract
The development of alcoholic liver disease (ALD) is a complex process involving both parenchymal and nonparenchymal cells resident in the liver. Although the mechanisms for ALD are not completely understood, it is clear that increased oxidative stress, and activation of the innate immune system are essential elements in the pathophysiology of ALD. Oxidative stress from ethanol exposure results from increased generation of reactive oxygen species and decreased hepatocellular antioxidant activity, including changes in the thioredoxin/peroxiredoxin family of proteins. Both cellular and circulating components of the innate immune system are activated by exposure to ethanol. For example, ethanol exposure enhances toll-like receptor-4 (TLR-4)-dependent cytokine expression by Kupffer cells, likely due, at least in part, to dysregulation of redox signaling. Similarly, complement activation in response to ethanol leads to increased production of the anaphylatoxins, C3a and C5a, and activation C3a receptor and C5a receptor. Complement activation thus contributes to increased inflammatory cytokine production and can influence redox signaling. Here we will review recent progress in understanding the interactions between oxidative stress and innate immunity in ALD. These data illustrate that ethanol-induced oxidative stress and activation of the innate immune system interact dynamically during ethanol exposure, exacerbating ethanol-induced liver injury. Antioxid. Redox Signal. 15, 523–534.
doi:10.1089/ars.2010.3746
PMCID: PMC3118704  PMID: 21126203
14.  Role of the multifunctional DNA repair and redox signaling protein Ape1/Ref-1 in cancer and endothelial cells: Small molecule inhibition of Ape1's redox function 
Antioxidants & redox signaling  2008;10(11):1853-1867.
The DNA base excision repair pathway is responsible for the repair of DNA damage caused by oxidation/alkylation and protects cells against the effects of endogenous and exogenous agents. Removal of the damaged base by creates a baseless (AP) site. AP endonuclease1 (Ape1) acts upon this site to continue the BER pathway repair. Failure to repair baseless sites leads to DNA strand breaks and cytotoxicity. In addition to Ape1's repair role, it also functions as a major redox signaling factor to reduce and activate transcription factors such as AP1, p53, HIF-1α and others which control the expression of genes important for cell survival and cancer promotion and progression. Thus the Ape1 protein interacts with proteins involved in DNA repair, growth signaling pathways and pathways involved in tumor promotion and progression. While knockdown studies using siRNA have been informative in studying the role of Ape1 in both normal and cancer cells, knocking down Ape1 does not reveal the individual role of Ape1's redox or repair functions. The identification of small molecule inhibitors of specific Ape1 functions is critical for mechanistic studies and translational applications. Here we discuss small molecule inhibition of Ape1 redox and its effect on both cancer and endothelial cells.
doi:10.1089/ars.2008.2120
PMCID: PMC2587278  PMID: 18627350
15.  Role of the Multifunctional DNA Repair and Redox Signaling Protein Ape1/Ref-1 in Cancer and Endothelial Cells: Small-Molecule Inhibition of the Redox Function of Ape1 
Antioxidants & Redox Signaling  2008;10(11):1853-1867.
Abstract
The DNA base excision-repair pathway is responsible for the repair of DNA damage caused by oxidation/alkylation and protects cells against the effects of endogenous and exogenous agents. Removal of the damaged base creates a baseless (AP) site. AP endonuclease1 (Ape1) acts on this site to continue the BER-pathway repair. Failure to repair baseless sites leads to DNA strand breaks and cytotoxicity. In addition to the repair role of Ape1, it also functions as a major redox-signaling factor to reduce and activate transcription factors such as AP1, p53, HIF-1α, and others that control the expression of genes important for cell survival and cancer promotion and progression. Thus, the Ape1 protein interacts with proteins involved in DNA repair, growth-signaling pathways, and pathways involved in tumor promotion and progression. Although knockdown studies with siRNA have been informative in studying the role of Ape1 in both normal and cancer cells, knocking down Ape1 does not reveal the individual role of the redox or repair functions of Ape1. The identification of small-molecule inhibitors of specific Ape1 functions is critical for mechanistic studies and translational applications. Here we discuss small-molecule inhibition of Ape1 redox and its effect on both cancer and endothelial cells. Antioxid. Redox Signal. 10, 1853–1867.
doi:10.1089/ars.2008.2120
PMCID: PMC2587278  PMID: 18627350
16.  Oxidant and redox signaling in vascular oxygen sensing: implications for systemic and pulmonary hypertension 
Antioxidants & redox signaling  2008;10(6):1137-1152.
It is well known for over hundred years that systemic blood vessels dilate to decreases in oxygen tension (hypoxia; low Po2) and this response appears to be critical to supply blood to the stressed organ. Conversely, pulmonary vessels constrict to a fall in alveolar Po2 in order to maintain a balance in ventilation-to-perfusion ratio. Currently, although there is little question that Po2 affects vascular reactivity and vascular smooth muscle cells (VSMC) act as oxygen sensors, the molecular mechanisms involved in modulating the vascular reactivity are still not clearly understood. Many laboratories including ours have suggested intracellular calcium concentration ([Ca2+]i), which regulates vasomotor function, is controlled by free radicals and redox signaling, including NAD(P)H and glutathione (GSH) redox. In this review article, therefore, we will discuss the implications of redox and oxidants alterations seen in pulmonary and systemic hypertension and how key targets that control [Ca2+]i such as ion channels, Ca2+ release from internal stores and uptake by the sarcoplasmic reticulum, and the Ca2+ sensitivity to the myofilaments, are regulated by changes in intracellular redox and oxidants associated with vascular Po2 sensing in physiological or pathophysiological conditions.
doi:10.1089/ars.2007.1995
PMCID: PMC2443404  PMID: 18315496
17.  Oxidant and Redox Signaling in Vascular Oxygen Sensing: Implications for Systemic and Pulmonary Hypertension 
Antioxidants & Redox Signaling  2008;10(6):1137-1152.
Abstract
It has been well known for >100 years that systemic blood vessels dilate in response to decreases in oxygen tension (hypoxia; low Po2), and this response appears to be critical to supply blood to the stressed organ. Conversely, pulmonary vessels constrict to a decrease in alveolar Po2 to maintain a balance in the ventilation-to-perfusion ratio. Currently, although little question exists that the Po2 affects vascular reactivity and vascular smooth muscle cells (VSMCs) act as oxygen sensors, the molecular mechanisms involved in modulating the vascular reactivity are still not clearly understood. Many laboratories, including ours, have suggested that the intracellular calcium concentration ([Ca2+ ]i), which regulates vasomotor function, is controlled by free radicals and redox signaling, including NAD(P)H and glutathione (GSH) redox. In this review article, therefore, we discuss the implications of redox and oxidant alterations seen in pulmonary and systemic hypertension, and how key targets that control [Ca2+ ]i, such as ion channels, Ca2+ release from internal stores and uptake by the sarcoplasmic reticulum, and the Ca2+ sensitivity to the myofilaments, are regulated by changes in intracellular redox and oxidants associated with vascular Po2 sensing in physiologic or pathophysiologic conditions. Antioxid. Redox Signal. 10, 1137–1152.
doi:10.1089/ars.2007.1995
PMCID: PMC2443404  PMID: 18315496
18.  Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection 
Antioxidants & Redox Signaling  2013;18(8):899-929.
Abstract
Significance: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. Recent Advances: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. Critical Issues: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. Future Directions: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation. Antioxid. Redox Signal. 00, 000–000.
doi:10.1089/ars.2012.4795
PMCID: PMC3557437  PMID: 22794198
19.  Reactive Oxygen Species and Thiol Redox Signaling in the Macrophage Biology of Atherosclerosis 
Antioxidants & Redox Signaling  2012;17(12):1785-1795.
Abstract
Significance: Despite the recent decline in the prevalence of cardiovascular diseases, atherosclerosis remains the leading cause of death in industrialized countries. Monocyte recruitment into the vessel wall is a rate-limiting step in atherogenesis. Death of macrophage-derived foam cells promotes lesion progression and the majority of acute complications of atherosclerotic disease (e.g., myocardial infarction) occur in lesions that are intensely infiltrated with monocyte-derived macrophages, underlining the critical roles monocytes and macrophages play in this complex chronic inflammatory disease. Recent Advances: A rapidly growing body of literature supports a critical role for reactive oxygen species (ROS) in the regulation of monocyte and macrophage (dys)function associated with atherogenesis and macrophage death in atherosclerotic plaque. Critical Issues: In this review we highlight the important roles of NADHP oxidase 4 recently identified in monocytes and macrophages and the role of ROS and (thiol) redox signaling in different aspects of monocytes and macrophage biology associated with atherosclerosis. Future Directions: Studies aimed at identifying the intracellular targets of ROS involved in redox signaling in macrophages and at elucidating the redox signaling mechanisms that control differentiation, activation, polarization, and death of monocytes and macrophages may ultimately lead to the development of novel preventive and therapeutic strategies for atherosclerosis. Antioxid. Redox Signal. 17, 1785–1795.
doi:10.1089/ars.2012.4638
PMCID: PMC3474194  PMID: 22540532
20.  Mitochondrial Energy and Redox Signaling in Plants 
Antioxidants & Redox Signaling  2013;18(16):2122-2144.
Abstract
Significance: For a plant to grow and develop, energy and appropriate building blocks are a fundamental requirement. Mitochondrial respiration is a vital source for both. The delicate redox processes that make up respiration are affected by the plant's changing environment. Therefore, mitochondrial regulation is critically important to maintain cellular homeostasis. This involves sensing signals from changes in mitochondrial physiology, transducing this information, and mounting tailored responses, by either adjusting mitochondrial and cellular functions directly or reprogramming gene expression. Recent Advances: Retrograde (RTG) signaling, by which mitochondrial signals control nuclear gene expression, has been a field of very active research in recent years. Nevertheless, no mitochondrial RTG-signaling pathway is yet understood in plants. This review summarizes recent advances toward elucidating redox processes and other bioenergetic factors as a part of RTG signaling of plant mitochondria. Critical Issues: Novel insights into mitochondrial physiology and redox-regulation provide a framework of upstream signaling. On the other end, downstream responses to modified mitochondrial function have become available, including transcriptomic data and mitochondrial phenotypes, revealing processes in the plant that are under mitochondrial control. Future Directions: Drawing parallels to chloroplast signaling and mitochondrial signaling in animal systems allows to bridge gaps in the current understanding and to deduce promising directions for future research. It is proposed that targeted usage of new technical approaches, such as quantitative in vivo imaging, will provide novel leverage to the dissection of plant mitochondrial signaling. Antioxid. Redox Signal. 18, 2122–2144.
doi:10.1089/ars.2012.5104
PMCID: PMC3698670  PMID: 23234467
21.  Superoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases 
Antioxidants & Redox Signaling  2011;15(6):1583-1606.
Abstract
Excessive reactive oxygen species Revised abstract, especially superoxide anion (O2•−), play important roles in the pathogenesis of many cardiovascular diseases, including hypertension and atherosclerosis. Superoxide dismutases (SODs) are the major antioxidant defense systems against O2•−, which consist of three isoforms of SOD in mammals: the cytoplasmic Cu/ZnSOD (SOD1), the mitochondrial MnSOD (SOD2), and the extracellular Cu/ZnSOD (SOD3), all of which require catalytic metal (Cu or Mn) for their activation. Recent evidence suggests that in each subcellular location, SODs catalyze the conversion of O2•− H2O2, which may participate in cell signaling. In addition, SODs play a critical role in inhibiting oxidative inactivation of nitric oxide, thereby preventing peroxynitrite formation and endothelial and mitochondrial dysfunction. The importance of each SOD isoform is further illustrated by studies from the use of genetically altered mice and viral-mediated gene transfer. Given the essential role of SODs in cardiovascular disease, the concept of antioxidant therapies, that is, reinforcement of endogenous antioxidant defenses to more effectively protect against oxidative stress, is of substantial interest. However, the clinical evidence remains controversial. In this review, we will update the role of each SOD in vascular biologies, physiologies, and pathophysiologies such as atherosclerosis, hypertension, and angiogenesis. Because of the importance of metal cofactors in the activity of SODs, we will also discuss how each SOD obtains catalytic metal in the active sites. Finally, we will discuss the development of future SOD-dependent therapeutic strategies. Antioxid. Redox Signal. 15, 1583–1606.
doi:10.1089/ars.2011.3999
PMCID: PMC3151424  PMID: 21473702
22.  Redox Signaling in an In Vivo Murine Model of Low Magnitude Oscillatory Wall Shear Stress 
Antioxidants & Redox Signaling  2011;15(5):1369-1378.
Abstract
Wall Shear Stress (WSS) has been identified as an important factor in the pathogenesis of atherosclerosis. We utilized a novel murine aortic coarctation model to acutely create a region of low magnitude oscillatory WSS in vivo. We employed this model to test the hypothesis that acute changes in WSS in vivo induce upregulation of inflammatory proteins, mediated by reactive oxygen species (ROS). Superoxide generation and VCAM-1 expression both increased in regions of low magnitude oscillatory WSS. WSS-dependent superoxide formation was attenuated by tempol treatment, but was unchanged in p47 phox knockout (ko) mice. However, in both the p47 phox ko mice and the tempol-treated mice, low magnitude oscillatory WSS produced an increase in VCAM-1 expression comparable to control mice. Additionally, this same VCAM-1 expression was observed in ebselen-treated mice and catalase overexpressing mice. These results suggest that although the redox state is important to the overall pathogenesis of atherosclerosis, the initial WSS-dependent inflammatory response leading to lesion localization is not dependent on ROS. Antioxid. Redox Signal. 15, 1369–1378.
doi:10.1089/ars.2010.3550
PMCID: PMC3144422  PMID: 20712414
23.  Age-Related Changes in Redox Signaling and VSMC Function 
Antioxidants & Redox Signaling  2010;12(5):641-655.
Abstract
Epidemiological studies have shown that advancing age is associated with an increased prevalence of cardiovascular disease (CVD). Vascular smooth muscle cells (VSMC) comprise the major arterial cell population, and changes in VSMC behavior, function, and redox status with age contribute to alterations in vascular remodeling and cell signaling. Over two decades of work on aged animal models provide support for age-related changes in VSMC and/or arterial tissues. Enhanced production of reactive oxygen species (ROS) and insufficient removal by scavenging systems are hallmarks of vascular aging. VSMC proliferation and migration are core processes in vascular remodeling and influenced by growth factors and signaling networks. The intrinsic link between gene regulation and aging often relates directly to transcription factors and their regulatory actions. Modulation of growth factor signaling leads to up- or downregulation of transcription factors that control expression of genes associated with VSMC proliferation, inflammation, and ROS production. Four major signaling pathways related to the transcription factors, AP-1, NF-κB, FoxO, and Nrf2, will be reviewed. Knowledge of age-related changes in signaling pathways in VSMC that lead to alterations in cell behavior and function consistent with disease progression may help in efforts to attenuate age-related CVD, such as atherosclerosis. Antioxid. Redox Signal. 12, 641–655.
doi:10.1089/ars.2009.2854
PMCID: PMC2864663  PMID: 19737090
24.  Autophagy, Redox Signaling, and Ventricular Remodeling 
Antioxidants & Redox Signaling  2009;11(8):1975-1988.
Abstract
Autophagy is a catabolic process through which damaged or long-lived proteins, macromolecules, or organelles are recycled by using lysosomal degradation machinery. Although the occurrence of autophagy in several cardiac diseases including ischemic or dilated cardiomyopathy, heart failure, hypertrophy, and during ischemia/reperfusion injury have been reported, the exact role of autophagy in these diseases is not known. Emerging studies indicate that oxidative stress in cellular system could induce autophagy, and oxidatively modified macromolecules and organelles can be selectively removed by autophagy. Mild oxidative stress–induced autophagy could provide the first line of protection against major damage like apoptosis and necrosis. Cardiac-specific loss of Atg5, an autophagic gene involved in the formation of autophagosome, causes cardiac hypertrophy, left ventricular dilation, and contractile dysfunction. Recently, it was revealed that Atg4, another autophagic gene involved in the formation of autophagosomes, is controlled through redox regulation under the condition of starvation-induced autophagy. In this review, we discuss the function of autophagy in association with oxidative stress and redox signaling in the remodeling of cardiac myocardium. Further research is needed to explore the possibilities of redox regulation of other autophagic genes and the role of redox signaling–mediated autophagy in the heart. Antioxid. Redox Signal. 11, 1975–1988.
doi:10.1089/ars.2009.2524
PMCID: PMC2848474  PMID: 19327038
25.  Redox Signaling Across Cell Membranes 
Antioxidants & Redox Signaling  2009;11(6):1349-1356.
Abstract
Generation of reactive oxygen species (ROS) by plasma membrane–localized NADPH oxidase (Nox 2) is a major mechanism of cell signaling associated with activation of the enzyme by a variety of agonists. With activation, the integral membrane flavocytochrome of Nox 2 transfers an electron from intracellular NADPH to extracellular O2, generating superoxide anion (O2•−). The latter dismutes to H2O2 which can diffuse through aquaporin channels in the plasma membrane to elicit an intracellular signaling response. O2•− also can initiate intracellular signaling by penetration of the cell membrane through anion channels (Cl- channel-3, ClC-3). Endosomes containing Nox2 and ClC-3 (called signaling endosomes) are composed of internalized plasma membrane and generate O2•− in the endosomal lumen to initiate signaling at intracellular sites. Thus, cellular signaling by Nox2 is dependent on the transmembrane flux of ROS. The role of this pathway has only recently been described and will require additional investigation to appreciate its physiological significance fully. Antioxid. Redox Signal. 11, 1349–1356.
doi:10.1089/ars.2008.2378
PMCID: PMC2842114  PMID: 19061438

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