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Vascular Oxidative Stress: Impact and Therapeutic Approaches

Cristina M. Sena, Adriana Leandro, Lara Azul and 2 more

Frontiers in Physiology · 2018 · Review

doi:10.3389/fphys.2018.01668

Abstract

Oxidative stress has been defined as an imbalance between oxidants and antioxidants and more recently as a disruption of redox signaling and control. It is generally accepted that oxidative stress can lead to cell and tissue injury having a fundamental role in vascular dysfunction. Physiologically, reactive oxygen species (ROS) control vascular function by modulating various redox-sensitive signaling pathways. In vascular disorders, oxidative stress instigates endothelial dysfunction and inflammation, affecting several cells in the vascular wall. Vascular ROS are derived from multiple sources herein discussed, which are prime targets for therapeutic development. This review focuses on oxidative stress in vascular physiopathology and highlights different strategies to inhibit ROS production.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Oxidative stress is an important underlying factor in health and disease. It is originated by an alteration in the balance of reactive oxygen species (ROS) production and antioxidant defense mechanisms. Homeostatic ROS concentrations play a crucial role as secondary messengers in many intracellular signaling pathways in both innate and adaptive immune responses. The problem occurs when ROS bioavailability overtakes the antioxidant defenses. In these conditions, ROS act as destructive agents affecting proteins, lipids and DNA, leading to cellular damage, tissue injury, and inflammation. On the other hand, from a mechanistic point of view, oxidative stress may be better defined as a disruption of redox signaling and control. This concept could redirect research to identify crucial perturbations of redox signaling and control and lead to new treatments for oxidative stress-related disease processes.

Oxidative stress has been associated with the pathogenesis of several chronic disorders such as neurodegenerative diseases, diabetes, hypercholesterolemia, and atherosclerosis and is a contributory pathogenic factor in obesity-related disorders. In addition, vascular oxidative stress is a leading cause in cardiovascular diseases. Elevated oxidative stress leads to vasoconstriction, vascular remodeling, inflammation, and fibrosis. Insufficient cellular protection against oxidative stress has been described as a major factor for the development of vascular diseases. Oxidative stress is also the principal cause of epigenetic changes that occur during aging.

The involvement of reactive oxygen and nitrogen species has been extensively studied in various pathological conditions. Its etiology is diverse.

This review focuses on the oxidative processes that occur mainly in the vasculature and lead to vascular dysfunction.

Vascular Oxidative Stress

Regulation of vascular tone is critical for the homeostatic function of blood vessels and blood supply to peripheral organs. In physiological conditions, maintenance of appropriate endothelial function provides vasorelaxant properties through release of vasoactive substances. An imbalance between production of vasoprotective and vasorelaxant factors and vasoconstrictor substances by the endothelium is a hallmark of endothelial dysfunction, which precedes numerous vascular pathologies. In this context, oxidative stress has a crucial role in the initiation and progression of endothelial dysfunction and vascular disease affecting several cells in the vascular wall.

In addition, vascular oxidative stress promotes systemic inflammation via immune activation. Activated immune cells migrate into the vasculature, and release several factors including ROS, metalloproteinases, cytokines, and chemokines that promote dysfunction and cause vascular damage promoting vasoconstriction and remodeling of blood vessels. Vascular remodeling, stiffness, structural elastin abnormalities, and increased oxidative stress are hallmarks of vascular damage in hypertension.

Endothelium

Endothelial cells regulate vascular tone having a crucial role in the control of organ vascular resistance. These cells, through their secretome, influence vascular smooth muscle cells (VSMCs) and circulating cells such as platelets and monocytes.

The arterial endothelium is subjected to various injurious stimuli such as oscillatory shear stress, disturbed turbulent flow and oxidative stress among others. The major ROS produced in response to several stimuli (such as hyperglycemia, hyperlipidemia, and hypertension) is superoxide anion that quickly combines with NO to produce peroxynitrite decreasing NO bioavailability and leading to endothelial dysfunction. In response, endothelial cells became activated, produce vasoconstrictor agents (thromboxane A2, endothelin-1, or prostaglandin H2) and an inflammatory response is initiated. The endothelium starts expressing adhesion molecules and secretes chemokines such as chemokine (C-C motif) ligand 2 (CCL2) to attract immune cells. The increased expression of chemokines and proteases in endothelial cells creates a vicious circle perpetuating the inflammatory response. During prolonged vascular inflammation, several changes such as an increment in apoptotic cells, remodeling of the extracellular matrix, breakdown of elastic lamella, and endothelial dysfunction, emerge in atheroprone vessels and accelerate atherosclerosis-related complications. Dysfunctional endothelium is crucial to initiate vascular dysfunction leading to several pathologic conditions including macro (atherosclerosis) and microvascular diseases.

Vascular Smooth Muscle Cells

Vasoactive substances exert their vasorelaxant or vasoconstrictive properties through effects on receptors of VSMCs, which are central for the regulation of vascular tone. These substances derive from endothelial cells, vasoactive nerves, and perivascular tissue.

Vascular smooth muscle cells can also be sources of ROS promoting oxidative stress. Various stimuli including increased cyclic stretch can promote oxidative stress in VSMCs. It was recently described that lysyl oxidase (LOX), an elastin crosslinking enzyme, is as a novel source of vascular ROS. LOX-derived ROS activate p38 mitogen-activated protein kinase critically influencing elastin structure and vessel stiffness in hypertension.

Activation of oxidative stress and inflammation occurs via receptors leading to changes in the balance between vasodilators and vasoconstrictors affecting vascular tone and ultimately lead to vascular dysfunction. Vascular ROS effects are mediated through redox-sensitive signaling pathways. ROS regulate protein kinases, phosphatases, mitogen-activated protein kinases, and transcription factors; playing an important role as modulators of [Ca2+]i, rho-associated coiled-coil protein kinase (ROCK), and the contractile machinery. Oxidative stress will activate protein kinase C (PKC) leading to the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and in turn increment oxidative stress. PKC activation will phosphorylate and activate multiple mechanisms that ultimately promote VSMCs contraction. Increased Nox-derived ROS generation enhances calcium signaling, up-regulates ROCK and modulates the actin cytoskeleton, thereby promoting vascular contraction and increasing vascular tone. PKC and ROCK activity play a role in exacerbated vasoconstriction associated with vascular dysfunction.

Adventitia and Perivascular Adipose Tissue

The adventitia surrounds the tunica media containing many different cell types in close continuity with perivascular tissue, particularly in large arteries, influencing both endothelial (through vasa vasorum) and VSMCs. In this context, perivascular adipose tissue (PVAT) is an important regulator of vasculature, with much more than a supportive and mechanical role it has also endocrine and paracrine functions. Visceral adipose tissue is a known source of adipokines but PVAT is also an active producer of both adipokines and inflammatory cytokines.

Under physiological conditions, PVAT has anti-contractile and anti-inflammatory properties that protect blood vessels. Recent studies have suggested that aortic PVAT is protective for endothelial dysfunction in hypercholesterolemic LDL receptor knockout mice. Elevated eNOS-derived NO production in aortic PVAT of this animal model is an adaptive mechanism that may protect endothelial function and maintain normal endothelium-dependent relaxation in the early stages of atherosclerotic disease.

In pathologic conditions such as obesity and atherosclerosis, PVAT changes its phenotype and can contribute to vascular oxidative stress because they have an increment in NADPH oxidases in adipocytes with increase activity in obesity-related conditions. In fact, an increment in ROS has been previously described. In addition, oxidative stress in adipocytes subsequently stimulates recruitment of immune cells. Perivascular adipocytes also express angiotensinogen and PVAT produces and releases angiotensin II and related peptides.

In obesity, PVAT displays hypoxia, inflammation, and oxidative stress culminating in a dysregulated production/secretion of adipokines and cytokines and leading to PVAT changes toward a proinflammatory phenotype. In animal models and in patients with obesity, PVAT phenotype has been described by up-regulation of pro-inflammatory adipokines/cytokines (e.g., leptin, interleukin-6, tumor necrosis factor-α) and down-regulation of anti-inflammatory adipokines/cytokines (e.g., adiponectin and Interleukin-10). In addition, an increment in esterified fatty acids has also been observed.

The oxidative stress and inflammation in PVAT have a major impact on endothelial function, vascular stiffness, smooth muscle migration and ultimately lead to vascular disease reinforcing the “vasocrine” effects of PVAT in obesity-related diseases.

Sources of Reactive Oxygen Species

In biological systems most ROS are generated from mitochondria. Mitochondrial dysfunction is an important cause in the development and progression of several diseases: energy surplus and oxidative stress causes the mitochondrial dysfunction fostering ROS production and oxidative stress. Other sources include NADPH oxidase, xanthine oxidase, cytochrome P450, uncoupled endothelial nitric oxide synthase (eNOS enzyme produces instead of NO), myeloperoxidases and lipoxygenases (Figure 1).

NADPH Oxidase

NADPH oxidases (Nox) are a crucial contributor to oxidative stress in vascular cells, including endothelial cells, VSMCs, fibroblasts, and perivascular adipocytes. Nox expression and activity are closely linked with clinical risk factors for atherosclerosis. There are at least seven variations of the Nox, characterized by their different catalytic subunits.

In blood vessels, Nox1 expression is residual under basal conditions and increases considerably after stimuli. Nox2 generates both and H2O2 directly affecting both NO bioavailability and contractile properties of the vasculature. Nox4 is expressed in all vascular and some perivascular cell types. Nox4 possesses vasorelaxant properties via eNOS activation. It predominantly produces H2O2 and only small amounts of. In the context of atherosclerosis, Nox4 expression appears to exert vasoprotective effects. Nox4 was shown to exert both a beneficial as well as detrimental effect, depending on the cell context and stimuli that influence its activity. Indeed, Nox4 is a source of ROS, which changes the redox-state of numerous proteins, and further research is needed to clarify its role in the vasculature. Nox 5 is also expressed in blood vessels. It is a Nox sensitive calcium isoform that produces. Nox 5 is a pro-contractile Nox isoform important in redox-sensitive contraction. It was recently described a novel function for vascular Nox5, linking calcium and ROS to the pro-contractile molecular machinery in VSMCs. Further studies are necessary to clarify Nox5 functions.

The renin-angiotensin system also stimulates NADPH oxidase activity contributing to oxidative stress, endothelial dysfunction, and structural vascular changes typical of hypertension and atherosclerosis.

The Mitochondrial Respiratory Chain

Mitochondrial oxidative phosphorylation produces, which is transformed to H2O2 by the manganese-dependent superoxide dismutase and subsequently to water by glutathione peroxidase 1. Under pathological conditions, due to insufficient ROS detoxification or excessive ROS production mitochondrial oxidative stress arises. Several diseases including atherosclerosis in human have been linked with mitochondrial dysfunction and subsequent oxidative stress.

Xanthine Oxidase

Endothelium dysfunction is linked with an increment in endothelial xanthine oxidase expression due to the increased production of superoxide and H2O2. The activity of this enzyme is increased in patients with coronary artery disease and inhibitors of this enzyme decrement endothelial dysfunction in both humans and animal models.

Uncoupled eNOS

Uncoupled eNOS generates instead of NO due to low levels of its cofactor tetrahydrobiopterin (BH4) or its substrate L-arginine. ROS, in particular peroxynitrite, promote eNOS “uncoupling”. Superoxide reacts with NO forming peroxynitrite that further oxidizes BH4 to dihydrobiopterin (BH2), creating a vicious circle and more eNOS uncoupling. Under physiological conditions, PVAT prevents eNOS uncoupling.

Myeloperoxidase

Myeloperoxidase (MPO) is an enzyme that belongs to the mammalian heme peroxidase superfamily, present in polymorphonuclear neutrophils and in monocytes/macrophages. MPO produces various compounds with pro-oxidant properties contributing to oxidative stress by oxidizing LDL and lowering NO bioavailability. This enzyme is involved in the formation of products derived from the oxidation of arachidonic acid that are involved in the inflammatory response and in lipid peroxidation. In addition, MPO promotes atherogenesis through the production of modified subtypes of LDL and HDL lipoproteins.

Lipoxygenases

Lipoxygenases (LOXs) are intracellular enzymes that peroxidize polyunsaturated fatty acids into bioactive lipids with a potential important role in the pathogenesis of atherosclerosis. LOXs, in particular 5-LOX and 12/15 LOX were found to be overexpressed in advanced atherosclerotic lesions. 5-LOX converts arachidonic acid into leukotriene B4, a potent chemo-attractant and leukocyte activator. However, inconclusive data were obtained with respect to the pathophysiological relevance of this leukotriene signaling in atherosclerosis. Thus, more studies are necessary to clarify this matter.

Antioxidant Defenses

In the vascular wall, the primary antioxidant defense systems to neutralize ROS production are enzymatic detoxifiers such as superoxide dismutases (MnSOD, CuZnSOD, EcSOD), catalase, glutathione peroxidase, paraoxonase, thioredoxin peroxidase, and heme oxygenases. In addition, the transcription factor nuclear factor erythroid-2 related factor 2 (Nrf2) has also been shown to play a key role in establishing a cellular anti-oxidant defense mechanism against oxidative stress and is consider an important therapeutic target to manage vascular dysfunction.

Therapeutics

Current pharmacological approaches for prevalent diseases, such as obesity, diabetes, and cardiovascular diseases are limited in efficacy. Many studies with antioxidants have proven unsuccessful in clinical trials. Hence, the search for new therapies is very important an emergent in order to improve the health status and increase lifespan of the patients.

Lifestyle Approaches

Lifestyle interventions are capable of reducing body weight through an increment in physical exercise and a reduction in caloric intake. Weight loss by calorie restriction and/or exercise can improve the global health state reducing oxidative stress.

Mitochondrial-Targeted Therapies

An important and potentially useful therapeutic approach for diseases associated with an increment in oxidative stress is to target antioxidants (as ubiquinol or α-tocopherol) to the mitochondria with lipophilic cations such as mitoquinone (MitoQ) or MitoE2. However, some studies revealed that MitoQ may be prooxidant and proapoptotic because its quinone group can participate in redox cycling and superoxide production. In light of these results, studies using mitoquinone as an antioxidant should be interpreted with caution.

In addition, enzymatic systems or cell-permeable cationic peptides (Szeto-Schiller peptides) directed to the mitochondria can also be an alternative therapeutic approach.

The mitochondrial protein p66Shc is fundamental in the homeostasis of mitochondria. Targeting this adaptor is another form of decreasing mitochondrial oxidative stress. P66Shc leads to ROS generation and its inactivation may be essential in oxidative stress related diseases. Previous studies have demonstrated that the expression of p66Shc is reduced by SIRT1 activation, which in turn decrements oxidative stress and endothelial dysfunction. SIRT mimetics are therefore promising tools to mitigate vascular disease progression.

Nrf2 Activators

Nrf2 is a transcription factor ubiquitously expressed in various tissues (including the vasculature) of human and animal models. It regulates the expression of several antioxidant and detoxification enzymes by binding to upstream antioxidant response elements.

This transcriptional factor is crucial in the prevention of oxidative stress related-diseases. Nrf2 interacts with antioxidant response element sequences of genes coding for antioxidant enzymes include γ-glutamyl cysteine ligase, NAD(P)H quinone oxidoreductase-1, glutathione S-transferase, heme oxygenase-1, uridine diphosphate glucuronosyl transferase, superoxide dismutase, catalase, and glutathione peroxidase-1 having a major role in cellular responses to oxidative stress.

Nrf2 activators can act through different mechanisms: they can directly prevent the interacting of Nrf2 with the Nrf2-binding site of Kelch-ECH-associated protein-1 (KEAP1) (as, for instance, ML334), they enhance transcription of Nrf2-targeted antioxidant genes (as berberine) or they specifically and reversibly increment Nrf2 half-life (as MG-132). Other compounds promote the release of Nrf2 from KEAP1 through interaction with its cysteine thiol residues (as sulforaphane).

Nox Inhibitors and Recouplers of eNOS

Triazolopyrimidines are efficient and selective inhibitors of NADPH oxidase activity. They specifically inhibit NADPH oxidase-derived ROS in vitro and have great potential in the field of atherosclerosis.

GKT137831, an inhibitor of NOx 1 and Nox4, reduces oxidative stress and diabetic vasculopathy and is currently under clinical trial. GLX351322 has been suggested as a therapeutic approach in type 2 diabetes through its selective inhibition of NOX4. In addition, rutin, a glycoside of quercetin, exhibits anti-oxidant and anti-inflammatory properties protecting endothelial dysfunction through inhibition of NOx4 and the ROS-sensitive NLRP3 inflammasome.

The aldehyde dehydrogenase 2 and its activator Alda-1 are novel molecules capable of inhibiting toxic aldehydes, decreasing oxidative stress and NADPH oxidase activity. These molecules are able to reverse mitochondria dysfunction having a potential role in atherogenesis. Nebivolol inhibits the activity of NADPH oxidase and, in addition, reverses eNOS uncoupling.

Inhibiting eNOS uncoupling is another strategy capable of reducing ROS. Among the drugs used in the clinical practice, inhibitors of the renin–angiotensin–aldosterone system, statins, metformin and pentaerythritol tetranitrate have been described to prevent or reverse eNOS uncoupling. Other compounds, such as resveratrol, sepiapterin, BH4, folic acid, α-lipoic acid and AVE3085, improve endothelial function through eNOS recoupling although further studies are needed to validate these compounds. Recently, thioredoxin was shown to reverse age-related hypertension and arterial stiffness by improving vascular redox and restoring eNOS function.

Targeting Hyperglycemic Memory

Inhibiting hyperglycemic memory concomitantly with a reduction in oxidative stress is crucial under diabetic conditions. The hyperglycemic memory needs to be reduced in diabetes in order to prevent the progression of diabetic complications. Otherwise, this occurrence will result in a vicious cycle continuously producing ROS and leading to vascular dysfunction. Targeting the incretin pathway with dipeptidyl peptidase inhibitors or glucagon-like peptide receptor-1 agonists was able to reduce advanced glycation end products (AGEs) and ROS downstream events that promote cellular damage. Therapies associated with reversion of hyperglycemic memory deserve further investigation in this field and include soluble RAGE/RAGE antagonists, AGE/methylglyoxal inhibitors, S100 inhibitors, targeting vascular protein lysine acetylation, among others.

Anti-diabetic Drugs

Studies both in humans and in animal models revealed that anti-diabetic drugs (such as metformin) are able to decrement oxidative stress and inflammation and ameliorate endothelial function reducing the progression toward atherosclerosis. Incretin mimetics, in particular GLP1 agonists and dipeptidyl peptidase-4 (DPP4) inhibitors, are currently anti-diabetic agents with a wide range of beneficial effects that include antioxidant effects. An example is linagliptin, an inhibitor of DPP4 that reduces obesity-related insulin resistance and inflammation by regulating M1/M2 macrophage status. It was recently shown that saxagliptin, an inhibitor of DPP4, prevented coronary vascular stiffness through a mechanism that involved a decrement in AGEs, NF-κB, and nitrotyrosine levels in aortic-banded mini swine.

In obesity, diabetes and hypertension mineralocorticoid receptor antagonism improves endothelial function and seems to be a mediator of the switch from vascular health to disease. In endothelial cells, the mineralocorticoid receptor exerts a protective role on endothelial function. In the presence of cardiovascular risk factors, endothelial mineralocorticoid receptor contributes to endothelial dysfunction through NOX activation, eNOS uncoupling, increased epithelial sodium channel expression, and ICAM1/VCAM1-mediated inflammation. Further studies are necessary to clarify these mechanisms.

PCSK-9 Inhibitors

PCSK9 inhibitors are monoclonal antibodies that bind to and inactivate proprotein convertase subtilisinkexin 9 (PCSK9), a liver enzyme that promotes the lysosomal degradation of LDL receptors in hepatocytes thus increasing the number of LDL receptors in the membrane and LDL-cholesterol uptake. In recent studies, evolocumab for 52 weeks significantly decreased the level of vitamin E in LDL-C and increased vitamin E level in HDL revealing antioxidant properties.

Other Pharmacological Approaches

Serotonin in peripheral blood reflects oxidative stress and plays an important role in atherosclerosis highlighting the novel anti-atherothrombotic strategy to mitigate vascular disease. Tropisetron, a 5-HT3 receptor antagonist, can attenuate early diabetes through calcineurin inhibition and by suppressing oxidative stress and some inflammatory cytokines in streptozotocin-induced diabetic rats.

More recently, cell-permeable peptides mimicking the kinase inhibitory region of suppressor of cytokine signaling- 1 (SOCS1) regulatory protein emerged as an important antioxidant and anti-inflammatory strategy to limit the progression of diabetic complications. SOCS-targeted therapies have recently been suggested as potential therapeutic approaches in atherosclerosis and deserve further investigation.

Other approach includes the inhibition of selenoprotein P (SeP). SeP is a liver derived secretory protein that promotes insulin resistance and is upregulated in the liver of type 2 diabetic patients. This hepatokine downregulates the metabolic switch, AMP-activated protein kinase (AMPK). Recent studies have suggested that SeP regulates cellular metabolism and the development of vascular diseases. SeP promotes vascular smooth cell proliferation through increased oxidative stress and mitochondrial dysfunction in an autocrine/paracrine manner. Sanguinarine, an orally active small molecule, reduces SeP expression and smooth muscle proliferation, and ameliorates pulmonary arterial hypertension in mice and rats. Thus, it seems that SeP could be a novel and realistic therapeutic target.

The clinical benefit of these compounds awaits further confirmation. Moreover, novel nanotherapeutic approaches are being developed to target oxidative stress and inflammation.

Traditional medicinal plants have been used by several civilizations through the years contributing to the notion that natural products are relevant sources of new pharmaceutical compounds. Technological advances are now capable of unravel the value of natural products as novel sources for new drug discovery including their role as antioxidants.

Conclusion

Vascular oxidative stress promotes endothelial dysfunction and atherosclerosis progression. In the vasculature, several sources promote an increment in oxidative stress.

Preventing vascular oxidative stress and incrementing NO bioavailability may represent the future therapeutic strategy to mitigate the cardiovascular burden and reduce associated risk factors.

Author Contributions

CS wrote the article. AL did bibliographic research. LA did bibliographic research. RS revised the manuscript. GP revised the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Molica F. Morel S. Kwak B. R. Rohner-Jeanrenaud F. Steffens S. (2015 ). Adipokines at the crossroad between obesity and cardiovascular disease. Thromb. Haemost. 113 553–566.

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    Munzel T. Gori T. (2009 ). Nebivolol: the somewhat-different beta adrenergic receptor blocker. J. Am. Coll. Cardiol. 54 1491–1499.

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    Pitanga T. N. de Aragão França L. Rocha V. C. Meirelles T. Borges V. M. Gonçalves M. S. (2014 ). Neutrophil-derived microparticles induce myeloperoxidase-mediated damage of vascular endothelial cells. BMC Cell Biol. 15:21.

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    Rodriguez-Porcel M. Chade A. R. Miller J. D. (2017 ). Studies on Atherosclerosis. Oxidative Stress in Applied Basic Research and Clinical Practice, 1st Edn. Berlin: Springer.

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    Sabatine M. S. Leiter L. A. Wiviott S. D. Giugliano R. P. Deedwania P. De Ferrari G. M. (2017 ). Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 5 941–950.

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    Sena C. M. Louro T. Matafome P. Nunes E. Monteiro P. Seiça R. (2009 ). Antioxidant and vascular effects of gliclazide in type 2 diabetic rats fed high-fat diet. Physiol. Res. 58 203–209.

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    Sena C. M. Nunes E. Louro T. Proença T. Fernandes R. Boarder M. R. (2008 ). Effects of alpha-lipoic acid on endothelial function in aged diabetic and high-fat fed rats. Br. J. Pharmacol. 153 894–906.

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    Serazin V. Dos Santos E. Morot M. Giudicelli Y. (2004 ). Human adipose angiotensinogen gene expression and secretion are stimulated by cyclic AMP via increased DNA cyclic AMP responsive element binding activity. Endocrine 25 97–104.

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    Smith R. A. Adlam V. J. Blaikie F. H. Manas A. R. Porteous C. M. James A. M. (2008 ). Mitochondria-targeted antioxidants in the treatment of disease. Ann. N. Y. Acad. Sci. 1147 105–111.

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    Spiekermann S. Landmesser U. Dikalov S. Bredt M. Gamez G. Tatge H. (2003 ). Electron spin resonance characterization of vascular xanthine and NAD(P) H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation 107 1383–1389.

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    Stachowicz A. Olszanecki R. Suski M. Wiśniewska A. Totoń-Żurańska J. Madej J. (2014 ). Mitochondrial aldehyde dehydrogenase activation by Alda-1 inhibits atherosclerosis and attenuates hepatic steatosis in apolipoprotein E-knockout mice. J. Am. Heart Assoc. 3:e001329.

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    Sugiura T. Dohi Y. Yamashita S. Hirowatari Y. Fujii S. Ohte N. (2016 ). Serotonin in peripheral blood reflects oxidative stress and plays a crucial role in atherosclerosis: novel insights toward holistic anti-atherothrombotic strategy. Atherosclerosis 246 157–160.

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    Suzuki T. Yamamoto M. (2017 ). Stress-sensing mechanisms and the physiological roles of the Keap1-Nrf2 system during cellular stress. J. Biol. Chem. 292 16817–16824.

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    Szeto H. H. (2006 ). Cell-permeable, mitochondrial-targeted, peptide antioxidants. AAPS J. 8 E277–E283.

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