• Users Online: 522
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2018  |  Volume : 5  |  Issue : 2  |  Page : 61-69

Molecular characterization of free radical function in redox signaling and strategies to reduce oxidative stress in cardiovascular diseases

Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Oromia, Ethiopia

Date of Submission25-Apr-2018
Date of Decision30-May-2018
Date of Acceptance10-Jun-2018
Date of Web Publication11-Sep-2018

Correspondence Address:
Dr. Leta Shiferaw Melaku
Department of Biomedical Sciences, College of Health Sciences, Arsi University, Asella, Oromia
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijcep.ijcep_21_18

Rights and Permissions

Free radicals are molecules with an unpaired electron. Due to the presence of free electron, these molecules are highly reactive. At moderate concentrations, free radicals play an important role as regulatory mediators in signaling molecules in a number of normal biochemical and physiological processes. Although there are several sources of vascular reactive oxygen species (ROS), the enzyme nicotinamide adenine dinucleotide phosphate oxidase is emerging as a strong candidate for excessive ROS production that is thought to lead to vascular oxidative stress. The implication of oxidative stress in the etiology of several cardiovascular diseases suggests that strategically, nonpharmacological and pharmacological therapy represents a promising avenue for treatment.

Keywords: Cardiovascular diseases, free radical, oxidative stress, reactive oxygen species

How to cite this article:
Melaku LS. Molecular characterization of free radical function in redox signaling and strategies to reduce oxidative stress in cardiovascular diseases. Int J Clin Exp Physiol 2018;5:61-9

How to cite this URL:
Melaku LS. Molecular characterization of free radical function in redox signaling and strategies to reduce oxidative stress in cardiovascular diseases. Int J Clin Exp Physiol [serial online] 2018 [cited 2019 Mar 20];5:61-9. Available from: http://www.ijcep.org/text.asp?2018/5/2/61/241034

  Introduction Top

In 1773, Lavoisier and Recherches de were the first to recognize that earth's atmosphere was composed of a vital substance (“air”) that supported life.[1] As the key life-supporting element, oxygen was independently discovered by Priestly, in 1775,[2] and Scheele, in 1777.[3] Within a few years of these seminal findings, oxygen toxic side effects that did not support life were also discovered. This revelation was made by Lavoisier in 1785 by a simple experiment in which guinea pigs exposed to oxygen in a container showed congestion of the right heart as well as lungs and died before the oxygen was fully utilized.[4] More than two centuries ago, the good and bad facets of oxygen that are played out by its unique molecular structure were already known.[5] The structural configuration of oxygen molecule is diradical that can accept four electrons and the resultant one-step tetravalent reduction results in the formation of water, with concurrent production of ATP. Ironically, if these four electrons are added one at a time, partially reduced forms of oxygen or free radicals are produced.[6],[7],[8] Free radicals can be defined as reactive chemical species having a single unpaired electron in an outer orbit.[9] This unstable configuration creates energy that can initiate autocatalytic reactions so that molecules to which they react are themselves converted into free radicals.[10] Although reactive oxygen species (ROS) are more common in biological systems,[10] free radicals also include reactive nitrogen species.[11] ROS are produced both endogenously and exogenously.[12] The endogenous sources of ROS are the mainly by-products formed in the cells of aerobic organisms within mitochondria.[13] Additional endogenous sources are certain enzymes, neutrophils, eosinophils, and macrophages.[10],[14],[15] In addition, microsomes and peroxisomes are the sources of ROS, and microsomes are responsible for the majority of ROS produced in vivo at hyperoxia sites.[16],[17] ROS can also be produced by a host of exogenous sources, such as xenobiotics, chlorinated compounds, environmental agents, metals (redox and nonredox), ions, and radiation.[10],[16],[18] In general, ROS commonly include superoxide anion (O2), hydrogen peroxide (H2O2), and hydroxyl radicals (OH·).[19],[20] It has been established that ROS can be both harmful and beneficial in biological systems depending on the environment.[21],[22] At normal physiological levels, in phagocytic cells, ROS play a key role in cell-mediated immunity and microbicidal activity.[23],[24]

In nonphagocytic cells, they are involved in a number of cellular signaling systems as well as in the induction or inhibition of cell proliferation.[25],[26],[27] The rate of ROS production in nonphagocytic cells is only about one-third of that of phagocytic cells.[28],[29],[30],[31] In contrast, at very high concentrations, ROS are often associated with the principle of oxidative stress.[32] The term oxidative stress is used to describe the condition of oxidative damage to a wide range of cellular structures, as a result of an imbalance between free radical production and antioxidant defenses.[33] Short-term oxidative stress may occur in tissues injured by trauma, infection, heat injury, hyperoxia, toxins, and excessive exercise.[34],[35] Moreover, harmful effects are balanced by the action of antioxidants, some of which are enzymes present in the body.[36] However, long-term oxidative stress despite the presence of the cell's antioxidant defense system, ROS have been implicated in the induction and complications of various cardiovascular diseases, such as atherosclerosis.[37],[38]

  The Role of Free Radicals in Redox Signaling Top

At normal physiological levels, free radicals are ideally suited to be signaling molecules because they are small and can diffuse short distances; there are several mechanisms for their production, and there are also numerous mechanisms for their rapid removal.[39] Furthermore, several enzymes which are involved in cell signaling mechanisms, such as guanylyl cyclase,[40] phospholipase C,[41],[42] phospholipase A2,[43],[44],[45],[46] and phospholipase D,[47] are also potential targets of ROS. Ion channels too may be targets,[48],[49] including calcium channels.[50] There are various examples of growth factors, cytokines, or other ligands that trigger ROS production in nonphagocytic cells through their corresponding membrane receptors. Such ROS production can mediate a positive feedback effect on signal transduction since intracellular signaling is often enhanced either by ROS or by a pro-oxidative shift of the intracellular thiol/disulfide redox state.[51] Signaling mechanisms that respond to changes in the thiol/disulfide redox state include AP-1 transcription factor in human T-cells, nuclear factor κB (NF-κB) transcription factor in human T-cells,[52] control of K + channel activity in the carotid body,[53] human insulin receptor kinase activity,[54] Src family kinases, JNK and p38 mitogen-activated protein kinase (MAPK) signaling pathways,[55] and signaling in replicative senescence.[56] Protein phosphorylation also plays a critical role in regulating many cellular metabolic processes in eukaryotes.

In particular, protein phosphorylation governs multiple signal transduction pathways.[57] Being a reversible and dynamic process, protein phosphorylation requires not only a PK but also a protein phosphatase (PP). Cellular target proteins are phosphorylated at specific cellular transduction sites (usually at serine/threonine or tyrosine residues) by one or more PKs, and the phosphates are removed by specific PPs. The extent of phosphorylation at a particular site can be regulated by changing the activity of either the PK or PP or both.[58] Among the extracellular signals, growth factor-dependent protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) are of primary importance to mitogenesis, cell adhesion, cell differentiation, oncogenic transformation, and apoptosis.[41],[54],[59] There has been a growing body of evidence, suggesting that ROS modulate PTK and PTP activities directly.[59],[60] ROS specifically H2O2 can be synthesized endogenously in certain cell types as a response to activation by specific cytokines or growth factors. This endogenous H2O2 then acts as a second messenger to stimulate PK cascades coupled to inflammatory gene expression or in control of the cell cycle.[61] The earliest convincing studies that implicated H2O2 as an endogenous messenger were performed by Sundaresan et al.[62] using, as a model system, vascular smooth muscle cells stimulated with platelet-derived growth factor (PDGF). PDGF receptor binding caused peroxide formation which could be inhibited by intracellular expression of catalase.[57] Catalase expression inhibited PDGF signal transduction by suppressing protein tyrosine phosphorylation. Antioxidants, particularly thiol-reducing agents such as N-acetyl-cysteine, could mimic the inhibitory effects of catalase and prevent redox activation of ligand-coupled PK cascades. Exposure to high concentrations of H2O2 or strong pro-oxidative changes in the intracellular thiol/disulfide redox state will generally lead to increased tyrosine phosphorylation in numerous proteins.[63],[64],[65],[66] This effect is to some extent, albeit not exclusively, the consequence of the oxidative inhibition of PTPs. Massive inhibition associated with increased net phosphorylation of receptor tyrosine kinases is induced by various types of strong oxidative stress, including high doses of ROS, ultraviolet irradiation, or alkylating agents.[67],[68],[69],[70],[71],[72],[73],[74] PTPs counteract the effect of PTKs and reset membrane receptors after ligand-induced autophosphorylation.[57]

The epidermal growth factor (EGF) receptor, for example, is normally dephosphorylated at all tyrosine residues in <1 min after ligand-induced autophosphorylation,[75] but this dephosphorylation is retarded by high concentrations of H2O2 on the order of 1 mM or other inducers of oxidative stress. A PTP was also shown to regulate the activation of the EGF receptor.[76] Reversible protein phosphorylation is the key biochemical event in most cell signaling pathways, and signal transduction involving ROS is no exception. Several reports have shown that MAPKs are activated by H2O2 in both animals [77],[78],[79] and plants,[80],[81],[82] which could lead to the modulation of gene expression. Whether H2O2 has a direct effect on MAPKs or activating upstream effectors needs to be established. On the other hand, H2O2 has also been shown to inhibit phosphatases, probably by the direct oxidation of cysteine in the active site of these enzymes.[79] The Janus kinase-signal transducers and activators of transcription pathways in animal cells are also activated by H2O2, suggesting that H2O2 may transduce its message into the nucleus of cells by at least two transduction pathways.[83] It is now becoming apparent that the redox status inside a cell is crucial to the correct functioning of many enzymes and can be used to alter enzyme activity; thus, alteration of the redox status could act as a signaling mechanism.[84] One of the most important redox-sensitive molecules in this respect must be glutathione (GSH), which forms the GSH–GSSG couple. Certainly, H2O2 will have the effect of lowering the GSH content of cells and altering the redox status, and hence, propagation of a signal induced by H2O2 through this route is likely. It is suggested that enzymes such as ribonucleotide reductase and thioredoxin reductase, as well as transcription factors, might be among the targets for altered redox status. Not only does GSH act as an antioxidant, but it also can modulate the activity of a variety of different proteins via S-glutathionylation of cysteine sulfhydryl groups. The thioredoxin system also makes a significant contribution to the redox environment by reducing inter- and intra-chain protein disulfide bonds as well as by maintaining the activity of important antioxidant enzymes such as peroxiredoxins and methionine sulfoxide reductases.[52],[85],[86] Baeuerle et al. and Rogler et al.[87],[88] showed that certain transcription factors of the NF-κB/rel family can be activated not only by receptor-targeted ligands but also by direct application of oxidizing agents (particularly H2O2) or ionizing radiation. Subsequently, several other PK cascades and transcription factors have been discovered to possess redox-sensitive elements.

The common paradigm in all redox-sensitive signal transduction pathways is the presence of intermediate PKs which are activated by phosphorylation of specific regulatory domains. For example, NF-κB is activated upon phosphorylation of an inhibitory subunit (IκB).[71],[87]

  Strategies to Reduce Oxidative Stress in Cardiovascular Diseases Top

Pharmacological inhibition of nicotinamide adenine dinucleotide phosphate oxidase

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has been reported to be the major source of O2 in the vascular tissue.[89] However, there is a lack of effective inhibitors targeting the NADPH oxidase system. Although diphenyleneiodonium is frequently used, it can inhibit a broad range of flavin-containing enzymes. Recently, several pharmacological and molecular approaches to directly target the NADPH oxidase enzyme have been proposed. Apocynin, a methoxy-substituted catechol, has been used by Peruvian Indians as an anti-inflammatory agent. It acts by blocking the assembly of p47 phox into the membrane complex.[90] Another study suggests that apocynin decreases O2 production in rat and human vascular rings, increases nitric oxide production in cultured human endothelial cells, and improves endothelial function ex vivo in human arteries and veins, as well as arteries from WKY and SHRSP rats.[91] Interestingly, effects of apocynin in young WKY rats (low oxidative stress) were minimal when compared with effects in age-matched SHRSP rats (high oxidative stress). It has also been reported that administration in vivo of apocynin to deoxycorticosterone acetate-salt hypertensive rats decreased both vascular O2 production and blood pressure.[92] Although apocynin appears to be an effective NADPH oxidase inhibitor in the vascular tissue from both rats and humans, it needs to be present in relatively high concentrations to be effective. Rey et al.[93] have also considered disruption of the active NADPH oxidase complex as a means of reducing oxidative stress. They used a chimeric peptide (gp91ds-tat) designed to cross cell membranes and then inhibit p47 phox association with gp91 phox. Infusion of this peptide into mice significantly inhibited Ang-II-induced rises in blood pressure and vascular O2 production.

Another recently developed compound, S17834, a benzo-(γ)-pyran-4-one, has been shown to inhibit NADPH oxidase activity and O2 production and attenuate atherosclerotic lesions in apolipoprotein-E-deficient mice.[94] However, its exact mechanism of action remains to be elucidated. Several studies have suggested that 3-hydroxy-3-methyl glutaryl-CoA reductase inhibitors (statins) have inhibitory actions on O2 production from NADPH oxidase-independent of low-density lipoprotein (LDL) reduction.[95],[96] It has been shown recently that both O2 and H2O2 production by vascular tissue and leukocytes are inhibited by simvastatin in Ang-II-infused rats.[97] Prevention of O2 production by statins may be linked to prenylation-dependent Rac translocation and NADPH oxidase inhibition.[98]

Pharmacological inhibition of the renin-angiotensin system

Ang II has been shown to be a potent stimulation of NADPH oxidase activity in the vascular smooth muscle, fibroblasts, endothelial cells, and cardiomyocytes. Infusions of Ang II have been shown to cause upregulation of the subunits of NADPH oxidase and increase O2 levels in animal studies.[99],[100],[101] There is accumulating evidence that Ang II is also an important stimulant of NADPH oxidase activity and O2 production in human.[102],[103],[104] In addition to its interactions with NADPH oxidase, Ang II has been shown to induce LOX-1 expression, the human endothelial receptor for oxidized LDL.[105] Thus, it is not surprising that angiotensin-converting enzyme (ACE) inhibition and Ang-II-receptor antagonisms may play a key role in reducing levels of oxidative stress. It has been commonly postulated since the Heart Outcomes Protection Study [106] that some of the beneficial effects of ACE inhibitors are independent of their effect on blood pressure. ACE inhibition as an antioxidant strategy has been suggested as part of the explanation for this. Consistent with this hypothesis, ACE inhibition has been shown to improve endothelial function in patients with coronary artery disease.[107] In addition, AT1-receptor antagonists have been shown to be antioxidant and vasoprotective in patients with coronary artery disease, again downregulating vascular NADPH oxidase expression.[108] Treatment with either an ACE inhibitor or an AT1-receptor antagonist resulted in lower levels of vascular O2.[109] It has been shown that calcium channel blockers, beta-blockers, and alpha-receptor blockers have antioxidant effects in conditions in vitro.

However, although a recent study by Baykal et al.[110] demonstrated a reduction in malondialdehyde and an increase in erythrocyte levels of superoxide dismutase (SOD) in hypertensives taking the ACE inhibitor ramipril or the AT1-receptor blocker valsartan, no improvement in the antioxidant status was observed in patients taking amlodipine (calcium channel blocker), metoprolol (beta-blocker), or doxazosin (alpha-blocker).

Antioxidant dietary supplements

A wealth of data from epidemiological studies suggest that a greater intake of antioxidant vitamins, such as Vitamin E, Vitamin C, and beta-carotene, are associated with a reduced risk of cardiovascular disease.[111] Numerous animal studies support this hypothesis [112],[113],[114] as do a number of relatively short-term functional studies in human although many of these studies employed supraphysiological concentrations of vitamins. Vitamin E has been shown to decrease LDL oxidation [115],[116] and to improve endothelial function.[117],[118] Similarly, Vitamin C administration has been shown to improve endothelium-dependent vasodilation.[119],[120] The exact molecular mechanisms underlying these beneficial effects are not fully understood, but some recent studies are beginning to elucidate potential pathways. Ulker et al.[121] reported that 24 h and exposure to Vitamin C (10–100 μM) or Vitamin E (100 μM) enhanced nitric oxide synthase (NOS) activity and attenuated NADPH oxidase activity in the rat aorta. It has been suggested that the Vitamin C-mediated increase in NOS activity could be related to alterations in tetrahydrobiopterin (BH4) levels.[122],[123] Consistent with this hypothesis, long-term treatment of apolipoprotein-E-deficient mice with Vitamin C resulted in a decrease in levels of 7,8-dihydrobiopterin (BH2), an oxidized form of BH4, and an improvement in the ratio of BH4/BH2.[124] Despite strong evidence demonstrating antioxidant effects of Vitamins C and E in animals, and acutely in human, prospective randomized clinical trials have produced contrasting results. Of the larger trials, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico,[125] the Heart Outcomes Prevention Evaluation,[106] the Heart Protection Study,[126] and the Primary Prevention Project [127] failed to show any benefit. In contrast, the Cambridge Heart Antioxidant Study [128] and most recently the Antioxidant Supplementation in Atherosclerosis Prevention Study [129] report positive results. Data from these and some smaller trials have been elegantly summarized in an editorial by Jialal and Devaraj.[115] Numerous explanations have been proposed for the lack of observed benefit in the majority of randomized trials.

They include oxidant stress status of the participants and dose and combination of vitamins administered. Vitamins C and E reside in different cellular compartments, supporting the concept of combined therapy. Moreover, Vitamin E may be oxidized to form the tocopherol radical. This radical can enhance lipid peroxidation and needs to be converted back into the reduced form by other antioxidants.[130] Although the role of the antioxidant vitamins remains controversial, it is widely accepted that a “healthy diet” has an important role in the prevention of cardiovascular disease. Two recent studies emphasize this. In one randomized placebo-controlled trial in which participants were encouraged to increase fruit and vegetable consumption, both systolic and diastolic blood pressure was significantly lower in the intervention group.[131] In the second study, 6 weeks of “Mediterranean diet,” but not oral Vitamin C, was shown to improve vascular function.[132] It is probable that antioxidant vitamins in the “healthy diet” act in synergy with other antioxidants, such as flavonoids and other phenolic compounds, to provide a better antioxidant environment than that achieved with vitamin supplementation alone. Recently, the beneficial effects of polyphenols, particularly from red wine, have received much attention.[133] Several studies have demonstrated antioxidant properties of red wine and purple grape juice.[134],[135] It has also been suggested that red wine polyphenols could act to improve endothelial function by increasing endothelial NOS (eNOS) expression.[136] However, it must be remembered that other beverages, including beer and green tea, have been reported to have oxidative potential as having a range of foodstuffs ranging from olive oil to nuts.[137] Such data support the recommendation of a diet rich in fruits, vegetables, whole grain, oils, and nuts for cardiovascular protection.

L-Arginine supplements

Numerous studies in both experimental animals and human have shown that acute and chronic administration of L-arginine improves vascular function in hypercholesterolemia and other forms of cardiovascular disease.[138],[139],[140] The availability of L-arginine for reaction with eNOS should not be rate limiting as intracellular levels of L-arginine are in the millimolar range, whereas the Km for the substrate is in the micromolar range. This apparent discrepancy is frequently referred to as the “L-arginine paradox.” Explanations for this paradox include decreased O2 production, decreased transport of arginine into endothelial cells, increased levels of asymmetric dimethylarginine, and increased insulin release.[141]

Most recently, it has been suggested that translational control of NOS expression by arginine can explain the arginine paradox, at least for inducible NOS (iNOS).[142]

Thiol-containing compounds supplements

Over the years, a number of thiol-containing compounds have been used experimentally to inhibit LDL oxidation and reduce oxidative stress. Recent studies would support the continued investigation of such compounds. In glucose-fed rats, α-lipoic acid attenuated hypertension, insulin resistance, and oxidative stress,[143] and in another study, it was shown to lower blood pressure in spontaneously hypertensive rats.[144] In human, the classical sulfhydryl compound N-acetyl-cysteine reduced cardiovascular events in patients with end-stage renal failure.[145]

Estrogen and hormone replacement therapy

Premenopausal women are at a lower risk of atherosclerosis and have a lower incidence of coronary heart disease and myocardial infarction than postmenopausal women or age-matched men.[146],[147] Acute estrogen administration has been reported to improve vasoreactivity in healthy postmenopausal women.[148],[149] Epidemiological studies suggested that hormone replacement therapy reduced morbidity and mortality associated with cardiovascular disease.[146] Innumerable animal studies have also shown favorable effects of estrogen on the cardiovascular system.[150],[151] However, controversy exists over the mechanisms underlying the beneficial effects of estrogen. Some groups have cited decreased O2 production as a primary cause [151],[152] and others increased expression of NOS by genomic or nongenomic pathways.[150],[153],[154],[155] In addition, estrogens may activate the gene encoding cyclooxygenase and decrease production of the potent vasoconstrictor endothelin.[156],[157] Surprisingly, against this background, data from recently published randomized prospective-controlled clinical trials failed to show cardiovascular benefit from hormone replacement therapy (Heart and Estrogen Progesterone Replacement Study,[158] Estrogen Replacement and Atherosclerosis,[159] and the Women's Health Initiative Randomized Controlled Trial [160]). Part of this apparent contradiction may relate to the cohorts studied. Most animal studies and most of the early observational studies used healthy cohorts which may not be representative of the general population. Women with existing cardiovascular disease may not show the same beneficial effects of estrogen on endothelial function as demonstrated in healthy cohorts.

In such women, the adverse effects of estrogen, such as the increase in triacylglycerol levels and C-reactive protein, may out weight the benefits.[158]

Pharmacological superoxide dismutase mimetics supplements

Endogenous O2 is dismutated to H2O2 by a family of SODs. In general, studies both in vivo and in vitro aimed at reducing oxidative stress by increasing levels of Cu/Zn SOD have proved disappointing. This may be because Cu/Zn SOD does not gain access to the appropriate cellular compartments. However, a number of SOD mimetics are available that cross the membrane and have proved more successful in decreasing oxidative stress and improving endothelial function.[161],[162]

Pharmacological inhibition of xanthine oxidase

Xanthine oxidase has been proposed to be an important source of O2 in human.[102] The enzyme exists in two isoforms, xanthine oxidase and xanthine dehydrogenase. Activity of the former may be increased in ischemia-reperfusion injury and inflammation. Cardillo et al.[163] reported that the xanthine oxidase inhibitor oxypurinol improved endothelial function in hypercholesterolemic, but not hypertensive, subjects. More recently, another xanthine oxidase inhibitor allopurinol has been shown to improve endothelial function in Type II diabetes, congenital heart failure, and cigarette smokers.[164],[165],[166] However, it must be noted that the patient numbers in all these studies were low (11 patients or less).

  Conclusion Top

Free radicals can be either harmful or helpful to the body. The concentration and location of ROS are the main determinants of their effect. Many data support the notion that ROS released from NADPH oxidase, myeloperoxidase, xanthine oxidase, lipoxygenase, and NOS. At normal physiological levels, free radicals ideally suited to be signaling molecules. Several enzymes which are involved in cell signaling mechanisms, ion channels, human insulin receptor kinase activity, Src family kinases, and JNK and p38 MAPK signaling pathways are also potential targets of ROS. There has been a growing body of evidence suggesting that ROS modulate PTK and PTP activities directly.

ROS production can mediate a positive feedback effect on signal transduction since intracellular signaling is often enhanced by ROS or by a pro-oxidative shift of the intracellular thiol/disulfide redox state. When an overload of free radicals cannot gradually be destroyed, their accumulation in the body generates a phenomenon called oxidative stress. This process plays a major part in the development of various cardiovascular diseases. A wealth of data from epidemiological studies suggests that greater intakes of antioxidant are associated with a reduced risk of cardiovascular disease. In the future, both nonpharmacological and pharmacological therapeutic strategy to increase the antioxidant capacity of cells may be used to fortify the long-term effective treatment. Further research is needed before this supplementation could be officially recommended as adjuvant therapy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Lavoisier A, Recherches de M. Priestly sur les differentes especes d'air. In: Opuscules Physiques et Chimiques, 1773. Ch. 15. Reprinted in Oeuvres De Lavoisier. Paris: Imprimerie Imperiale; 1864.  Back to cited text no. 1
Priestly J. Experiments and Observations on Different Kinds of Air. Reprinted in “The discovery of oxygen,” Part 1, Vol. 2. Sec 3-5. Alembic Club Reprint No. 7. London: Simpkin, Marshall, Hamilton, Kent; 1894. p. 29-203.  Back to cited text no. 2
Scheele C. Chemische abhandlung von der luft und dem Feuer, Upsala and Leipzig. 1777. Reprinted as “The Discovery of Oxygen,” Part 2. Alembic Club Reprint No. 8. London: Gurney and Jackson; 1923.  Back to cited text no. 3
Lavoisier A. Alterations qu'eprouve l'air resire. Recueil des memoires de Lavoisier. Read to the Societe de Medicine. ReprRepinted as part of “Memoires sur la Respirationet al. Transpiration des Animaux” in 'Les Maitres de la Pensee Scientifique. Paris: Gauthier-Villaus et Cie.; 1785.  Back to cited text no. 4
McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 1969;244:6049-55.  Back to cited text no. 5
Halliwell B. Oxidants and human disease: Some new concepts. FASEB J 1987;1:358-64.  Back to cited text no. 6
Singal PK, Petkau A, Gerrard JM, Hrushovetz S, Foerster J. Free radicals in health and disease. Mol Cell Biochem 1988;84:121-2.  Back to cited text no. 7
Kaul N, Siveski-Iliskovic N, Hill M, Slezak J, Singal PK. Free radicals and the heart. J Pharmacol Toxicol Methods 1993;30:55-67.  Back to cited text no. 8
Riley PA. Free radicals in biology: Oxidative stress and the effects of ionizing radiation. Int J Radiat Biol 1994;65:27-33.  Back to cited text no. 9
Rahman K. Studies on free radicals, antioxidants, and co-factors. Clin Interv Aging 2007;2:219-36.  Back to cited text no. 10
Miller AA, Budzyn K, Sobey CG. Vascular dysfunction in cerebrovascular disease: Mechanisms and therapeutic intervention. Clin Sci (Lond) 2010;119:1-7.  Back to cited text no. 11
Cadenas E. Biochemistry of oxygen toxicity. Annu Rev Biochem 1989;58:79-110.  Back to cited text no. 12
Inoue M, Sato EF, Nishikawa M, Park AM, Kira Y, Imada I, et al. Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr Med Chem 2003;10:2495-505.  Back to cited text no. 13
Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 2004;266:37-56.  Back to cited text no. 14
Conner EM, Grisham MB. Inflammation, free radicals, and antioxidants. Nutrition 1996;12:274-7.  Back to cited text no. 15
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006;160:1-40.  Back to cited text no. 16
Gupta M, Dobashi K, Greene E, Orak J, Singh I. Studies on hepatic injury and antioxidant enzyme activities in rat sub-cellular organelles following in vivo ischemia and reperfusion. Mol Cell Biochem 1997;176:337-47.  Back to cited text no. 17
Leonard SS, Harris GK, Shi X. Metal-induced oxidative stress and signal transduction. Free Radic Biol Med 2004;37:1921-42.  Back to cited text no. 18
Gutteridge JM. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 1995;41:1819-28.  Back to cited text no. 19
Cadenas E, Sies H. The lag phase. Free Radic Res 1998;28:601-9.  Back to cited text no. 20
Lopaczynski W, Zeisel S. Antioxidants, programmed cell death, and cancer. Nutr Res 2001;21:295-307.  Back to cited text no. 21
Glade M. The role of reactive oxygen species in health and disease northeast regional environmental public health centre University of Massachusetts. Amerst Nutr 2003;19:401-3.  Back to cited text no. 22
Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003;52:1-8.  Back to cited text no. 23
Gaut JP, Yeh GC, Tran HD, Byun J, Henderson JP, Richter GM, et al. Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis. Proc Natl Acad Sci U S A 2001;98:11961-6.  Back to cited text no. 24
Tyrrell RM, Applegate LA, Tromvoukis Y. The proximal promoter region of the human heme oxygenase gene contains elements involved in stimulation of transcriptional activity by a variety of agents including oxidants. Carcinogenesis 1993;14:761-5.  Back to cited text no. 25
Um HD, Orenstein JM, Wahl SM. Fas mediates apoptosis in human monocytes by a reactive oxygen intermediate dependent pathway. J Immunol 1996;156:3469-77.  Back to cited text no. 26
Bolwell GP, Butt VS, Davies DR, Zimmerlin A. The origin of the oxidative burst in plants. Free Radic Res 1995;23:517-32.  Back to cited text no. 27
Zweier JL, Broderick R, Kuppusamy P, Thompson-Gorman S, Lutty GA. Determination of the mechanism of free radical generation in human aortic endothelial cells exposed to anoxia and reoxygenation. J Biol Chem 1994;269:24156-62.  Back to cited text no. 28
Thannickal VJ, Fanburg BL. Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1. J Biol Chem 1995;270:30334-8.  Back to cited text no. 29
Bae YS, Kang SW, Seo MS, Baines IC, Tekle E, Chock PB, et al. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem 1997;272:217-21.  Back to cited text no. 30
Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, et al. Cell transformation by the superoxide-generating oxidase mox1. Nature 1999;401:79-82.  Back to cited text no. 31
Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, et al. Oxygen radicals and human disease. Ann Intern Med 1987;107:526-45.  Back to cited text no. 32
Rock CL, Jacob RA, Bowen PE. Update on the biological characteristics of the antioxidant micronutrients: Vitamin C, Vitamin E, and the carotenoids. J Am Diet Assoc 1996;96:693-702.  Back to cited text no. 33
McCord JM. The evolution of free radicals and oxidative stress. Am J Med 2000;108:652-9.  Back to cited text no. 34
Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev 2010;4:118-26.  Back to cited text no. 35
Halliwell B. Antioxidants in human health and disease. Ann Rev Nutr 1996;16:33-50.  Back to cited text no. 36
Rao A, Bharani M, Pallavi V. Role of antioxidants and free radicals in health and disease. Adv Pharmacol Toxicol 2006;7:29-38.  Back to cited text no. 37
Rahman K. Garlic and aging: New insights into an old remedy. Ageing Res Rev 2003;2:39-56.  Back to cited text no. 38
Santos-Buelga C, Scalbert A. Proanthocyanidins and tannin-like compounds in human nutrition. J Food Sci Agric 2000;80:1094-117.  Back to cited text no. 39
Griendling KK, Sorescu D, Lassègue B, Ushio-Fukai M. Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 2000;20:2175-83.  Back to cited text no. 40
Cheng Y, Zhao Q, Liu X, Araki S, Zhang S, Miao J, et al. Phosphatidylcholine-specific phospholipase C, p53 and ROS in the association of apoptosis and senescence in vascular endothelial cells. FEBS Lett 2006;580:4911-5.  Back to cited text no. 41
Zhao J, Miao J, Zhao B, Zhang S. Upregulating of fas, integrin beta4 and P53 and depressing of PC-PLC activity and ROS level in VEC apoptosis by safrole oxide. FEBS Lett 2005;579:5809-13.  Back to cited text no. 42
Krjukov AA, Semenkova GN, Cherenkevich SN, Gerein V. Activation of redox-systems of monocytes by hydrogen peroxide. Biofactors 2006;26:283-92.  Back to cited text no. 43
Bergamini C, Seghieri G. ROS and kidney disease in the evolution from acute phase to chronic end stage disease: A commentary on “Oxidative signaling in renal epithelium: Critical role of cPLA2 and p38SAPK.” Free Radic Biol Med 2006;15:190-2.  Back to cited text no. 44
Akiyama N, Nabemoto M, Hatori Y, Nakamura H, Hirabayashi T, Fujino H, et al. Up-regulation of cytosolic phospholipase A2alpha expression by N, N-diethyldithiocarbamate in PC12 cells; involvement of reactive oxygen species and nitric oxide. Toxicol Appl Pharmacol 2006;215:218-27.  Back to cited text no. 45
Adibhatla RM, Hatcher JF. Altered lipid metabolism in brain injury and disorders. Subcell Biochem 2008;49:241-68.  Back to cited text no. 46
Tappia PS, Dent MR, Dhalla NS. Oxidative stress and redox regulation of phospholipase D in myocardial disease. Free Radic Biol Med 2006;41:349-61.  Back to cited text no. 47
Thomas MP, Chartrand K, Reynolds A, Vitvitsky V, Banerjee R, Gendelman HE, et al. Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: Relevance for the pathogenesis of Parkinson's disease. J Neurochem 2007;100:503-19.  Back to cited text no. 48
Moudgil R, Michelakis ED, Archer SL. The role of k+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: Implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation 2006;13:615-32.  Back to cited text no. 49
Hajnóczky G, Csordás G, Das S, Garcia-Perez C, Saotome M, Sinha Roy S, et al. Mitochondrial calcium signalling and cell death: Approaches for assessing the role of mitochondrial ca2+ uptake in apoptosis. Cell Calcium 2006;40:553-60.  Back to cited text no. 50
Allen RG, Tresini M. Oxidative stress and gene regulation. Free Radic Biol Med 2000;28:463-99.  Back to cited text no. 51
Galter D, Mihm S, Dröge W. Distinct effects of glutathione disulphide on the nuclear transcription factor kappa B and the activator protein-1. Eur J Biochem 1994;221:639-48.  Back to cited text no. 52
Acker H, Xue D. Mechanisms of oxygen sensing in the carotid body in comparison to other oxygen sensing cells. News Physiol Sci 1995;10:211-6.  Back to cited text no. 53
Schmid E, El Benna J, Galter D, Klein G, Dröge W. Redox priming of the insulin receptor beta-chain associated with altered tyrosine kinase activity and insulin responsiveness in the absence of tyrosine autophosphorylation. FASEB J 1998;12:863-70.  Back to cited text no. 54
Hehner SP, Breitkreutz R, Shubinsky G, Unsoeld H, Schulze-Osthoff K, Schmitz ML, et al. Enhancement of T cell receptor signaling by a mild oxidative shift in the intracellular thiol pool. J Immunol 2000;165:4319-28.  Back to cited text no. 55
Smith J, Ladi E, Mayer-Proschel M, Noble M. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci U S A 2000;97:10032-7.  Back to cited text no. 56
Genestra M. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell Signal 2007;19:1807-19.  Back to cited text no. 57
Hunter T. 1001 protein kinases redux – Towards 2000. Semin Cell Biol 1994;5:367-76.  Back to cited text no. 58
Chiarugi P, Fiaschi T. Redox signalling in anchorage-dependent cell growth. Cell Signal 2007;19:672-82.  Back to cited text no. 59
Charest A, Wilker EW, McLaughlin ME, Lane K, Gowda R, Coven S, et al. ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice. Cancer Res 2006;66:7473-81.  Back to cited text no. 60
Marciniak A, Borkowska E, Kedra A, Rychlik M, Beltowski J. Time-dependent transition from H(2)O(2)-extracellular signal-regulated kinase- to O(2)-nitric oxide-dependent mechanisms in the stimulatory effect of leptin on renal na+/K+/-ATPase in the rat. Clin Exp Pharmacol Physiol 2006;33:1216-24.  Back to cited text no. 61
Sundaresan M, Yu ZX, Ferrans VJ, Irani K, Finkel T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 1995;270:296-9.  Back to cited text no. 62
Staal FJ, Anderson MT, Staal GE, Herzenberg LA, Gitler C, Herzenberg LA, et al. Redox regulation of signal transduction: Tyrosine phosphorylation and calcium influx. Proc Natl Acad Sci U S A 1994;91:3619-22.  Back to cited text no. 63
Hardwick JS, Sefton BM. Activation of the Lck tyrosine protein kinase by hydrogen peroxide requires the phosphorylation of tyr-394. Proc Natl Acad Sci U S A 1995;92:4527-31.  Back to cited text no. 64
Chiang GG, Sefton BM. Phosphorylation of a Src kinase at the autophosphorylation site in the absence of Src kinase activity. J Biol Chem 2000;275:6055-8.  Back to cited text no. 65
Wang Y, Johnson P. Expression of CD45 lacking the catalytic protein tyrosine phosphatase domain modulates lck phosphorylation and T cell activation. J Biol Chem 2005;280:14318-24.  Back to cited text no. 66
Sullivan SG, Chiu DT, Errasfa M, Wang JM, Qi JS, Stern A, et al. Effects of H2O2 on protein tyrosine phosphatase activity in HER14 cells. Free Radic Biol Med 1994;16:399-403.  Back to cited text no. 67
Bender K, Blattner C, Knebel A, Iordanov M, Herrlich P, Rahmsdorf HJ, et al. UV-induced signal transduction. J Photochem Photobiol B 1997;37:1-7.  Back to cited text no. 68
Barrett W, DeGnore J, Konig S, Fales H, Keng Y, Zhang Z, et al. Roles of superoxide radical anion in signal transduction mediated by reversible regulation of protein tyrosine phosphates 1B. Biochemistry 1999;38:6699-705.  Back to cited text no. 69
Meng TC, Fukada T, Tonks NK. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell 2002;9:387-99.  Back to cited text no. 70
Wang Q, Dubé D, Friesen RW, LeRiche TG, Bateman KP, Trimble L, et al. Catalytic inactivation of protein tyrosine phosphatase CD45 and protein tyrosine phosphatase 1B by polyaromatic quinones. Biochemistry 2004;43:4294-303.  Back to cited text no. 71
Cho SH, Lee CH, Ahn Y, Kim H, Kim H, Ahn CY, et al. Redox regulation of PTEN and protein tyrosine phosphatases in H(2)O(2) mediated cell signaling. FEBS Lett 2004;560:7-13.  Back to cited text no. 72
Wu X, Zhu L, Zilbering A, Mahadev K, Motoshima H, Yao J, et al. Hyperglycemia potentiates H(2)O(2) production in adipocytes and enhances insulin signal transduction: Potential role for oxidative inhibition of thiol-sensitive protein-tyrosine phosphatases. Antioxid Redox Signal 2005;7:526-37.  Back to cited text no. 73
Groen A, Lemeer S, van der Wijk T, Overvoorde J, Heck AJ, Ostman A, et al. Differential oxidation of protein-tyrosine phosphatases. J Biol Chem 2005;280:10298-304.  Back to cited text no. 74
Knebel A, Rahmsdorf HJ, Ullrich A, Herrlich P. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J 1996;15:5314-25.  Back to cited text no. 75
Qu CK, Yu WM, Azzarelli B, Feng GS. Genetic evidence that shp-2 tyrosine phosphatase is a signal enhancer of the epidermal growth factor receptor in mammals. Proc Natl Acad Sci U S A 1999;96:8528-33.  Back to cited text no. 76
Bełtowski J, Marciniak A, Jamroz-Wiśniewska A, Borkowska E. Nitric oxide – Superoxide cooperation in the regulation of renal Na(+), K(+)-ATPase. Acta Biochim Pol 2004;51:933-42.  Back to cited text no. 77
Dasari A, Bartholomew JN, Volonte D, Galbiati F. Oxidative stress induces premature senescence by stimulating caveolin-1 gene transcription through p38 mitogen-activated protein kinase/Sp1-mediated activation of two GC-rich promoter elements. Cancer Res 2006;66:10805-14.  Back to cited text no. 78
Lu D, Chen J, Hai T. The regulation of ATF3 gene expression by mitogen-activated protein kinases. Biochem J 2007;401:559-67.  Back to cited text no. 79
Aruoma OI, Colognato R, Fontana I, Gartlon J, Migliore L, Koike K, et al. Molecular effects of fermented papaya preparation on oxidative damage, MAP kinase activation and modulation of the benzo[a] pyrene mediated genotoxicity. Biofactors 2006;26:147-59.  Back to cited text no. 80
Kalbina I, Strid A. The role of NADPH oxidase and MAP kinase phosphatase in UV-B-dependent gene expression in Arabidopsis. Plant Cell Environ 2006;29:1783-93.  Back to cited text no. 81
Ichimura K, Casais C, Peck SC, Shinozaki K, Shirasu K. MEKK1 is required for MPK4 activation and regulates tissue-specific and temperature-dependent cell death in Arabidopsis. J Biol Chem 2006;281:36969-76.  Back to cited text no. 82
Di Bona D, Cippitelli M, Fionda C, Cammà C, Licata A, Santoni A, et al. Oxidative stress inhibits IFN-alpha-induced antiviral gene expression by blocking the JAK-STAT pathway. J Hepatol 2006;45:271-9.  Back to cited text no. 83
Adler A, Vescovo P, Robinson JK, Kritzer MF. Gonadectomy in adult life increases tyrosine hydroxylase immunoreactivity in the prefrontal cortex and decreases open field activity in male rats. Neuroscience 1999;89:939-54.  Back to cited text no. 84
Arnér ES, Holmgren A. The thioredoxin system in cancer. Semin Cancer Biol 2006;16:420-6.  Back to cited text no. 85
Gon S, Beckwith J. Ribonucleotide reductases: Influence of environment on synthesis and activity. Antioxid Redox Signal 2006;8:773-80.  Back to cited text no. 86
Baeuerle PA. IkappaB-NF-kappaB structures: At the interface of inflammation control. Cell 1998;95:729-31.  Back to cited text no. 87
Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T, et al. Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 1998;115:357-69.  Back to cited text no. 88
Griendling KK, Ushio-Fukai M. NADH/NADPH oxidase and vascular function. Trends Cardiovasc Med 1997;7:301-7.  Back to cited text no. 89
Meyer JW, Holland JA, Ziegler LM, Chang MM, Beebe G, Schmitt ME, et al. Identification of a functional leukocyte-type NADPH oxidase in human endothelial cells: A potential atherogenic source of reactive oxygen species. Endothelium 1999;7:11-22.  Back to cited text no. 90
Hamilton CA, Brosnan MJ, Al-Benna S, Berg G, Dominiczak AF. NAD(P)H oxidase inhibition improves endothelial function in rat and human blood vessels. Hypertension 2002;40:755-62.  Back to cited text no. 91
Beswick RA, Dorrance AM, Leite R, Webb RC. NADH/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat. Hypertension 2001;38:1107-11.  Back to cited text no. 92
Rey FE, Cifuentes ME, Kiarash A, Quinn MT, Pagano PJ. Novel competitive inhibitor of NAD(P)H oxidase assembly attenuates vascular O(2)(-) and systolic blood pressure in mice. Circ Res 2001;89:408-14.  Back to cited text no. 93
Cayatte AJ, Rupin A, Oliver-Krasinski J, Maitland K, Sansilvestri-Morel P, Boussard MF, et al. S17834, a new inhibitor of cell adhesion and atherosclerosis that targets NADPH oxidase. Arterioscler Thromb Vasc Biol 2001;21:1577-84.  Back to cited text no. 94
Wagner AH, Köhler T, Rückschloss U, Just I, Hecker M. Improvement of nitric oxide-dependent vasodilatation by HMG-coA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 2000;20:61-9.  Back to cited text no. 95
Yasunari K, Maeda K, Minami M, Yoshikawa J. HMG-coA reductase inhibitors prevent migration of human coronary smooth muscle cells through suppression of increase in oxidative stress. Arterioscler Thromb Vasc Biol 2001;21:937-42.  Back to cited text no. 96
Delbosc S, Cristol JP, Descomps B, Mimran A, Jover B. Simvastatin prevents angiotensin II-induced cardiac alteration and oxidative stress. Hypertension 2002;40:142-7.  Back to cited text no. 97
Wassmann S, Laufs U, Bäumer AT, Müller K, Konkol C, Sauer H, et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: Involvement of angiotensin AT1 receptor expression and rac1 GTPase. Mol Pharmacol 2001;59:646-54.  Back to cited text no. 98
Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA, Harrison DG, et al. Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 1997;95:588-93.  Back to cited text no. 99
Cifuentes ME, Rey FE, Carretero OA, Pagano PJ. Upregulation of p67(phox) and gp91(phox) in aortas from angiotensin II-infused mice. Am J Physiol Heart Circ Physiol 2000;279:H2234-40.  Back to cited text no. 100
Wang HD, Xu S, Johns DG, Du Y, Quinn MT, Cayatte AJ, et al. Role of NADPH oxidase in the vascular hypertrophic and oxidative stress response to angiotensin II in mice. Circ Res 2001;88:947-53.  Back to cited text no. 101
Berry C, Hamilton CA, Brosnan MJ, Magill FG, Berg GA, McMurray JJ, et al. Investigation into the sources of superoxide in human blood vessels: Angiotensin II increases superoxide production in human internal mammary arteries. Circulation 2000;101:2206-12.  Back to cited text no. 102
Guzik TJ, West NE, Black E, McDonald D, Ratnatunga C, Pillai R, et al. Vascular superoxide production by NAD(P)H oxidase: Association with endothelial dysfunction and clinical risk factors. Circ Res 2000;86:E85-90.  Back to cited text no. 103
Touyz RM, He G, Deng LY, Schiffrin EL. Role of extracellular signal-regulated kinases in angiotensin II-stimulated contraction of smooth muscle cells from human resistance arteries. Circulation 1999;99:392-9.  Back to cited text no. 104
Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K, et al. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation 1999;100:899-902.  Back to cited text no. 105
Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000;342:154-60.  Back to cited text no. 106
Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on reversing ENdothelial dysfunction) study. Circulation 1996;94:258-65.  Back to cited text no. 107
Rueckschloss U, Quinn MT, Holtz J, Morawietz H. Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: Protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2002;22:1845-51.  Back to cited text no. 108
Berry C, Anderson N, Kirk AJ, Dominiczak AF, McMurray JJ. Renin angiotensin system inhibition is associated with reduced free radical concentrations in arteries of patients with coronary heart disease. Heart 2001;86:217-20.  Back to cited text no. 109
Baykal Y, Yilmaz MI, Celik T, Gok F, Rehber H, Akay C, et al. Effects of antihypertensive agents, alpha receptor blockers, beta blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium channel blockers, on oxidative stress. J Hypertens 2003;21:1207-11.  Back to cited text no. 110
Rimm EB, Stampfer MJ. Antioxidants for vascular disease. Med Clin North Am 2000;84:239-49.  Back to cited text no. 111
Crawford RS, Kirk EA, Rosenfeld ME, LeBoeuf RC, Chait A. Dietary antioxidants inhibit development of fatty streak lesions in the LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol 1998;18:1506-13.  Back to cited text no. 112
Davidge ST, Ojimba J, McLaughlin MK. Vascular function in the Vitamin E-deprived rat: An interaction between nitric oxide and superoxide anions. Hypertension 1998;31:830-5.  Back to cited text no. 113
Terasawa Y, Ladha Z, Leonard SW, Morrow JD, Newland D, Sanan D, et al. Increased atherosclerosis in hyperlipidemic mice deficient in alpha-tocopherol transfer protein and Vitamin E. Proc Natl Acad Sci U S A 2000;97:13830-4.  Back to cited text no. 114
Jialal I, Devaraj S. Antioxidants and atherosclerosis: Don't throw out the baby with the bath water. Circulation 2003;107:926-8.  Back to cited text no. 115
Gotoh N, Noguchi N, Tsuchiya J, Morita K, Sakai H, Shimasaki H, et al. Inhibition of oxidation of low density lipoprotein by Vitamin E and related compounds. Free Radic Res 1996;24:123-34.  Back to cited text no. 116
Green D, O'Driscoll G, Rankin JM, Maiorana AJ, Taylor RR. Beneficial effect of Vitamin E administration on nitric oxide function in subjects with hypercholesterolaemia. Clin Sci (Lond) 1998;95:361-7.  Back to cited text no. 117
Heitzer T, Ylä Herttuala S, Wild E, Luoma J, Drexler H. Effect of Vitamin E on endothelial vasodilator function in patients with hypercholesterolemia, chronic smoking or both. J Am Coll Cardiol 1999;33:499-505.  Back to cited text no. 118
Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 1998;97:2222-9.  Back to cited text no. 119
Hornig B, Arakawa N, Kohler C, Drexler H. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998;97:363-8.  Back to cited text no. 120
Ulker S, McKeown PP, Bayraktutan U. Vitamins reverse endothelial dysfunction through regulation of eNOS and NAD(P)H oxidase activities. Hypertension 2003;41:534-9.  Back to cited text no. 121
Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER, et al. L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem 2001;276:40-7.  Back to cited text no. 122
Huang A, Vita JA, Venema RC, Keaney JF Jr. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem 2000;275:17399-406.  Back to cited text no. 123
d'Uscio LV, Milstien S, Richardson D, Smith L, Katusic ZS. Long-term Vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res 2003;92:88-95.  Back to cited text no. 124
Dietary supplementation with n-3 polyunsaturated fatty acids and Vitamin E after myocardial infarction: Results of the GISSI-prevenzione trial. Gruppo Italiano per lo studio della sopravvivenza nell'infarto miocardico. Lancet 1999;354:447-55.  Back to cited text no. 125
Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7-22.  Back to cited text no. 126
De Caterina R. The primary prevention project study group. Low-dose aspirin and Vitamin E in people at cardiovascular risk: A randomized trial in general practice. Ital Heart J Suppl 2001;2:681-4.  Back to cited text no. 127
Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ, et al. Randomised controlled trial of Vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS) Lancet 1996;347:781-6.  Back to cited text no. 128
Salonen RM, Nyyssönen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen TH, et al. Six-year effect of combined Vitamin C and E supplementation on atherosclerotic progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. Circulation 2003;107:947-53.  Back to cited text no. 129
Landmesser U, Harrison DG. Oxidant stress as a marker for cardiovascular events: Ox marks the spot. Circulation 2001;104:2638-40.  Back to cited text no. 130
John JH, Ziebland S, Yudkin P, Roe LS, Neil HA; Oxford Fruit and Vegetable Study Group, et al. Effects of fruit and vegetable consumption on plasma antioxidant concentrations and blood pressure: A randomised controlled trial. Lancet 2002;359:1969-74.  Back to cited text no. 131
Singh N, Graves J, Taylor PD, MacAllister RJ, Singer DR. Effects of a 'healthy' diet and of acute and long-term Vitamin C on vascular function in healthy older subjects. Cardiovasc Res 2002;56:118-25.  Back to cited text no. 132
Wollin SD, Jones PJ. Alcohol, red wine and cardiovascular disease. J Nutr 2001;131:1401-4.  Back to cited text no. 133
Frankel EN, Kanner J, German JB, Parks E, Kinsella JE. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993;341:454-7.  Back to cited text no. 134
Stein JH, Keevil JG, Wiebe DA, Aeschlimann S, Folts JD. Purple grape juice improves endothelial function and reduces the susceptibility of LDL cholesterol to oxidation in patients with coronary artery disease. Circulation 1999;100:1050-5.  Back to cited text no. 135
Leikert JF, Räthel TR, Wohlfart P, Cheynier V, Vollmar AM, Dirsch VM, et al. Red wine polyphenols enhance endothelial nitric oxide synthase expression and subsequent nitric oxide release from endothelial cells. Circulation 2002;106:1614-7.  Back to cited text no. 136
Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, et al. Bioactive compounds in foods: Their role in the prevention of cardiovascular disease and cancer. Am J Med 2002;113 Suppl 9B:71S-88S.  Back to cited text no. 137
Böger RH, Bode-Böger SM, Mügge A, Kienke S, Brandes R, Dwenger A, et al. Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production. Atherosclerosis 1995;117:273-84.  Back to cited text no. 138
Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J, et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996;97:1989-94.  Back to cited text no. 139
Tousoulis D, Davies G, Tentolouris C, Crake T, Toutouzas P. Coronary stenosis dilatation induced by L-arginine. Lancet 1997;349:1812-3.  Back to cited text no. 140
Loscalzo J. What we know and don't know about L-arginine and NO. Circulation 2000;101:2126-9.  Back to cited text no. 141
Lee J, Ryu H, Ferrante RJ, Morris SM Jr., Ratan RR. Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci U S A 2003;100:4843-8.  Back to cited text no. 142
El Midaoui A, de Champlain J. Prevention of hypertension, insulin resistance, and oxidative stress by alpha-lipoic acid. Hypertension 2002;39:303-7.  Back to cited text no. 143
Vasdev S, Ford CA, Parai S, Longerich L, Gadag V. Dietary alpha-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive rats. J Hypertens 2000;18:567-73.  Back to cited text no. 144
Tepel M, van der Giet M, Statz M, Jankowski J, Zidek W. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: A randomized, controlled trial. Circulation 2003;107:992-5.  Back to cited text no. 145
Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses' health study. N Engl J Med 1991;325:756-62.  Back to cited text no. 146
Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka LF, et al. Guide to primary prevention of cardiovascular diseases. A statement for healthcare professionals from the task force on risk reduction. American heart association science advisory and coordinating committee. Circulation 1997;95:2329-31.  Back to cited text no. 147
Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO 3rd. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994;90:786-91.  Back to cited text no. 148
Pinto S, Virdis A, Ghiadoni L, Bernini G, Lombardo M, Petraglia F, et al. Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women. Hypertension 1997;29:268-73.  Back to cited text no. 149
Huang A, Sun D, Koller A, Kaley G. 17beta-estradiol restores endothelial nitric oxide release to shear stress in arterioles of male hypertensive rats. Circulation 2000;101:94-100.  Back to cited text no. 150
Barbacanne MA, Rami J, Michel JB, Souchard JP, Philippe M, Besombes JP, et al. Estradiol increases rat aorta endothelium-derived relaxing factor (EDRF) activity without changes in endothelial NO synthase gene expression: Possible role of decreased endothelium-derived superoxide anion production. Cardiovasc Res 1999;41:672-81.  Back to cited text no. 151
Wagner AH, Schroeter MR, Hecker M. 17beta-estradiol inhibition of NADPH oxidase expression in human endothelial cells. FASEB J 2001;15:2121-30.  Back to cited text no. 152
Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M, et al. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res 2000;87:677-82.  Back to cited text no. 153
Mendelsohn ME. Nongenomic, ER-mediated activation of endothelial nitric oxide synthase: How does it work? What does it mean? Circ Res 2000;87:956-60.  Back to cited text no. 154
Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK, et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000;407:538-41.  Back to cited text no. 155
Akishita M, Ouchi Y, Miyoshi H, Orimo A, Kozaki K, Eto M, et al. Estrogen inhibits endothelin-1 production and c-fos gene expression in rat aorta. Atherosclerosis 1996;125:27-38.  Back to cited text no. 156
Bilsel AS, Moini H, Tetik E, Aksungar F, Kaynak B, Ozer A, et al. 17Beta-estradiol modulates endothelin-1 expression and release in human endothelial cells. Cardiovasc Res 2000;46:579-84.  Back to cited text no. 157
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and estrogen/progestin replacement study (HERS) research group. JAMA 1998;280:605-13.  Back to cited text no. 158
Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-9.  Back to cited text no. 159
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the women's health initiative randomized controlled trial. JAMA 2002;288:321-33.  Back to cited text no. 160
Bouloumié A, Bauersachs J, Linz W, Schölkens BA, Wiemer G, Fleming I, et al. Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production. Hypertension 1997;30:934-41.  Back to cited text no. 161
Fontana L, McNeill KL, Ritter JM, Chowienczyk PJ. Effects of Vitamin C and of a cell permeable superoxide dismutase mimetic on acute lipoprotein induced endothelial dysfunction in rabbit aortic rings. Br J Pharmacol 1999;126:730-4.  Back to cited text no. 162
Cardillo C, Kilcoyne CM, Cannon RO 3rd, Quyyumi AA, Panza JA. Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. Hypertension 1997;30:57-63.  Back to cited text no. 163
Guthikonda S, Sinkey C, Barenz T, Haynes WG. Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers. Circulation 2003;107:416-21.  Back to cited text no. 164
Butler R, Morris AD, Belch JJ, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 2000;35:746-51.  Back to cited text no. 165
Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 2002;106:221-6.  Back to cited text no. 166


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
   The Role of Free...
   Strategies to Re...

 Article Access Statistics
    PDF Downloaded163    
    Comments [Add]    

Recommend this journal