Reactive oxygen species and endothelial function in diabetes

European Journal of Pharmacology 636 (2010) 8–17

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European Journal of Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j p h a r

Review

Reactive oxygen species and endothelial function in diabetes Zahra Fatehi-Hassanabad a,⁎, Catherine B. Chan a, Brian L. Furman b a b

Departments of Physiology and Agricultural, Food and Nutritional Sciences, 6-126B Health Research Innovation Facility, University of Alberta, Edmonton, AB, Canada T6G 2R3 Strathclyde Institute of Pharmacy & Biomedical Sciences John Arbuthnott Building, 27 Taylor Street, Glasgow, G4 UK

a r t i c l e

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Article history: Received 16 November 2009 Received in revised form 27 February 2010 Accepted 22 March 2010 Available online 2 April 2010 Keywords: Reactive oxygen species Endothelial function Diabetes

a b s t r a c t An increasing body of evidence suggests that oxidant stress is involved in the pathogenesis of many cardiovascular diseases, including hypercholesterolemia, atherosclerosis, hypertension, heart failure and diabetes. Recent studies have also provided important new insights into potential mechanisms underlying the pathogenesis of vascular disease induced by diabetes. Glycosylation of proteins and lipids, which can interfere with their normal function, activation of protein kinase C with subsequent alteration in growth factor expression, promotion of inflammation through the induction of cytokine secretion and hyperglycemia-induced oxidative stress are some of these mechanisms. It is widely accepted that hyperglycemia-induced reactive oxygen species contribute to cell and tissue dysfunction in diabetes. A variety of enzymatic and non-enzymatic sources of reactive oxygen species exist in the blood vessels. These include NADPH oxidase, mitochondrial electron transport chain, xanthine oxidase and nitric oxide synthase. The present article reviews the effects of reactive oxygen species on endothelial function in diabetes and addresses possible therapeutic interventions. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactive oxygen and nitrogen species . . . . . . . . . . . . . . . 2.1. Reactive oxygen species . . . . . . . . . . . . . . . . . . 2.2. Reactive nitrogen species . . . . . . . . . . . . . . . . . . 3. The vascular endothelium and its function . . . . . . . . . . . . . 4. The sources of reactive oxygen species in endothelial cells . . . . . 4.1. Mitochondrial reactive oxygen species production . . . . . 4.2. Nonphagocytic NADPH oxidases . . . . . . . . . . . . . . 4.3. Xanthine oxidase . . . . . . . . . . . . . . . . . . . . . 4.4. Endothelial nitric oxide synthase . . . . . . . . . . . . . 4.5. Cytochrome P450 . . . . . . . . . . . . . . . . . . . . . 5. Reactive oxygen species generation in diabetes . . . . . . . . . . . 5.1. Direct effects of glucose and free fatty acids . . . . . . . . 5.2. Advanced glycation end products (AGEs) . . . . . . . . . . 6. Effects of reactive oxygen species on endothelial function in diabetes 7. Therapeutic interventions . . . . . . . . . . . . . . . . . . . . 7.1. Novel approaches to antioxidant therapy . . . . . . . . . . 8. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

⁎ Corresponding author. E-mail address: [email protected] (Z. Fatehi-Hassanabad). 0014-2999/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2010.03.048

Reactive oxygen and nitrogen species (ROS and RNS) are products of normal cellular metabolism and can produce either beneficial or harmful effects. The beneficial effects of reactive oxygen species occur

Z. Fatehi-Hassanabad et al. / European Journal of Pharmacology 636 (2010) 8–17

at low concentrations and involve physiological roles in host defense mechanism (against infectious agents) and in a number of cellular signaling systems. The harmful effects of reactive oxygen and nitrogen species, known as oxidative and nitrosative stress, are the result of an overproduction of reactive oxygen/nitrogen species and/or a deficiency of antioxidant mechanisms. In other words, oxidative stress results from the metabolic reactions that use oxygen and represents a disturbance in the equilibrium status of pro-oxidant versus antioxidant reactions. Excess reactive oxygen species can damage cellular DNA, lipids, and protein, thereby inhibiting their normal function. Cellular enzyme systems are potential sources of reactive oxygen species, including NADPH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide (NO) synthase (eNOS), arachidonic acid metabolizing enzymes including cytochrome P-450 enzymes, lipoxygenase and cyclooxygenase, and the mitochondrial respiratory chain (Griendling, 2005; Mueller et al., 2005). The relative contribution of individual sources may depend on the tissues and cells involved. There is strong evidence that diabetes/hyperglycaemia results a state of oxidative stress and that reactive oxygen species contribute to the production of insulin resistance, β-cell dysfunction and both the microvascular and macrovascular long-term complications of diabetes (Baynes, 1991; Wright et al., 2006; Forbes et al., 2008; Esper et al., 2008). The number of patients with diabetes is expected to reach 300 million by 2025 and thus the worldwide health impact of diabetes mellitus and its complications is enormous. Novel approaches are required to prevent and treat diabetes and to reduce the impact of its complications. This review considers the general properties and production of reactive oxygen species, examines the available evidence for their roles in endothelial dysfunction in diabetes and considers some therapeutic interventions.

2. Reactive oxygen and nitrogen species 2.1. Reactive oxygen species Free radicals are molecules containing one or more unpaired electrons. Because of the unpaired electrons, free radicals have a high degree of reactivity. Free radicals derived from oxygen represent the most important class of radical species. Superoxide anion (O•2−), the primary reactive oxygen species, causes contraction of vascular smooth muscle (Bharadwaj and Prasad, 2002; Langenstroer and Pieper, 1992) and scavenges nitric oxide within the vascular wall, reducing its biological half-life (Graier et al., 1999). Superoxide can interact with other molecules to generate secondary reactive oxygen species, either directly or prevalently through enzyme or metal catalysed processes. In mammalian cells, mitochondrial ATP production takes place mainly in enzyme complexes coupled to the electron transport chain (McIntyre et al., 1999). During energy transduction, a small number of electrons leak out, forming the free radical superoxide. Superoxide is produced from both complexes I and III of the electron transport chain (Miwa et al., 2003), and in its anionic form can readily cross the inner mitochondrial membrane. Excessive production of superoxide under stress conditions releases free iron from iron-containing molecules such as hemoglobin. This released iron can generate hydroxyl radical (through the Fenton reaction) (Fenton, 1894; Liochev, 1999; Thomas et al., 2009). The hydroxyl radical, •OH, has a very short half-life (about 10−9 s) and indiscriminately oxidizes its closest targets (Kehrer, 2000). Aikens and Dix (1991) demonstrated that in lipid membranes, hydroperoxyl radical initiates fatty acid peroxidation by fatty acid hydroperoxide-independent and -dependent pathways. H2O2 is a small, uncharged, and nonradical reactive oxygen species and can freely diffuse through cellular membranes (Halliwell, 1992). In physiological states, H2O2 is produced from oxygen by peroxisomes. Peroxisomes participate in several metabolic functions that use oxygen. If peroxisomes are damaged and their H2O2 consuming enzymes are

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downregulated, H2O2 will be released into cytosol, significantly contributing to oxidative stress. 2.2. Reactive nitrogen species Nitric oxide, a small molecule that contains one unpaired electron, is a free radical. Nitric oxide is generated in different tissues by specific nitric oxide synthases, which metabolise arginine to citrulline and nitric oxide (Palmer et al., 1988). Nitric oxide is an abundant reactive radical that acts as an important signalling molecule in a large variety of physiological processes, including regulation of blood pressure, neurotransmission, immune regulation (Moncada and Higgs, 1995; Moncada et al., 1991). Nitric oxide is soluble in aqueous and lipid media and it rapidly diffuses through the cytoplasm and plasma membranes. In an inflammatory state, such as obesity, the immune system produces both superoxide and nitric oxide, which may react together to produce significant amount of peroxynitrite anion (ONOO−). Peroxynitrite is a potent oxidizing agent that can cause DNA fragmentation and lipid peroxidation (Pacher et al., 2007). 3. The vascular endothelium and its function The endothelium, the largest organ in the body, is a single layer of cells that line the luminal surface of blood vessels. Since the seminal discovery of endothelial derived relaxing factor (EDRF) (Furchgott and Zawadzki, 1980) it has become increasingly apparent that the endothelium is far more than just a structural lining. It acts as a direct interface between the components of circulating blood and regulates numerous local blood vessel functions such as vascular tone, coagulation and inflammation (Cook, 2000) through the release of several mediators and/or activation of transcription factors. These include endotheliumderived relaxing factors (such as nitric oxide, endothelium derived hyperpolarizing factor (EDHF) and prostacyclin) and contracting factors (such as endothelin-1, thromboxane A2 and reactive oxygen species) as well as inflammatory modulators/mediators. Nitric oxide can be inactivated by reactive oxygen species and stabilized by superoxide dismutase (Jernigan et al., 2004; Rubanyi and Vanhoutte, 1986). In health, a critical balance exists between these mediators. In impaired endothelial function, this delicate balance is disrupted; the vasculature is predisposed to vasoconstriction, leukocyte adherence and vascular inflammation (Deanfield et al., 2007). Endothelial dysfunction, initially identified as impaired vasodilation to specific stimuli, is often associated with other abnormalities of endothelial function. Inflammatory cytokines, lipopolysaccharide, ischemia-reperfusion, physical trauma and diabetes are able to induce endothelial dysfunction. Endothelial dysfunction is implicated in the pathophysiology of several cardiovascular diseases such as hypertension (Endemann and Schiffrin, 2004), atherosclerosis (Ross, 1993) and type 2 diabetes mellitus (Browne et al., 2003). Indeed, disturbances in the vascular endothelium are a fundamental component in the development of diabetic microvascular and macrovascular complications, although other cell types (mesangial cells, podocytes) are also involved. 4. The sources of reactive oxygen species in endothelial cells The important sources of reactive oxygen species generation in endothelial cells include the mitochondrial enzyme complexes and the electron transport chain, NADPH oxidase, xanthine oxidase, uncoupled endothelial nitric oxide synthase and cytochrome P450. 4.1. Mitochondrial reactive oxygen species production Oxidative phosphorylation is the most critical function of mitochondria. The system of oxidative phosphorylation includes five large multienzyme complexes, namely, complexes, I, II, III, IV and ATP synthase. In normal physiological conditions and in most tissues, this

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system is an important source of reactive oxygen species (Turrens, 2003; Muller, 2000). Since reactive oxygen species are produced mainly in mitochondria, it appears that mitochondria are a primary target for their destructive actions (Droge, 2002; Balaban et al., 2005). This leads to mitochondrial damage, including a decreased mitochondrial ATP synthase, dysregulation of intracellular lipid homeostasis and induction of the mitochondrial permeability transition pores. This can potentially decrease the functional activity and even the quantity of mitochondria in cells and could lead to necrosis and apoptosis in cells. Excess production of reactive oxygen species from mitochondria has been implicated in the pathogenesis of aging (Raha and Robinson, 2000) and several diseases (Trushina and McMurray, 2007; Parihar and Brewer, 2007). However, in general, vascular endothelial cells exhibit low metabolic activity (Pagano et al., 1997), so mitochondrial reactive oxygen species may be less important than other sources.

dysfunction in which NADPH oxidase may play an important role (Zhang et al., 2009a,b).

4.2. Nonphagocytic NADPH oxidases

4.4. Endothelial nitric oxide synthase

NADPH oxidase is a multi-subunit enzyme that catalyzes superoxide production by the reduction of O2 using NADPH or NADH as the electron donor. NADPH oxidase was originally discovered in neutrophils, where it is a potent source of superoxide during phagocytosis and has an important role in nonspecific host defense. However, the NADPH oxidase is present in nonphagocytic cells such as endothelial cells, vascular smooth muscle cells, fibroblasts, and some other cells (Geiszt, 2006; Zalba et al., 2001; Yang et al., 2001a,b). Nonphagocytic NADPH oxidase produces low amount of reactive oxygen species which influence vascular cell growth, migration, proliferation, and activation (Cai, 2005; Touyz et al., 2003). This physiological NADPH oxidasederived reactive oxygen species has been implicated in the regulation of vascular tone by modulating vasodilation directly (Shimokawa and Matoba, 2004) or indirectly by decreasing nitric oxide bioavailability through the formation of ONOO− from superoxide (Kajiya et al., 2007). This constitutively active oxidase also responds to growth factors, hormones, including angiotensin II, and cytokines such as tumour necrosis factor α (TNFα) (Gertzberg et al., 2004; Li and Shah, 2003; Griendling et al., 2000). For instance, in endothelial and vascular smooth muscle cells, angiotensin II-dependent elevation of intracellular Ca2+ were increased by NADPH oxidase activation (Kappert et al., 2000; Hu et al., 2000). These effects of NADPH oxidase are mediated through redox-sensitive regulation of multiple signaling molecules and second messengers including mitogen-activated protein kinases, protein tyrosine phosphatases, tyrosine kinases, proinflammatory genes, ion channels, and Ca2+ (Hool and Corry, 2007; Kimura et al., 2005; Yoshioka et al., 2006). Low levels of NADPH oxidase activity are important in generating antioxidant defense mechanisms through the transcription factor NrF2 (NF-E2-related factor-2) and its binding to the antioxidant response element (ARE) (Gao and Mann, 2009). Nrf2 is a transactivator of genes containing an ARE in their promoter. Such genes encode a number of enzymes including NADPH:quinone oxidoreductase, glutathione S-transferases and aldo-keto reductases that have an important role in the protection of cells against oxidative stress (Xue et al., 2008). However, if nonphagocytic NADPH oxidase is upregulated, higher amounts of ROS may result in oxidative stress. For instance, NADPH oxidase is the major enzymatic source of reactive oxygen species in hypertension (Zalba et al., 2005), inflammation (Li and Shah, 2004; Ray and Shah, 2005), and ischemia-reperfusion injury (Griendling et al., 2000). It was also reported that diabetes is associated with an increase in NADPH oxidase-derived reactive oxygen species generation in humans (Guzik et al., 2000). In these pathological conditions, NADPH oxidase activation occurs over the short term through phosphorylation of the enzyme subunits and over the long term by increased subunit expression (Li and Shah, 2004; Ray and Shah, 2005). A very recent study showed that increased reactive oxygen species generation in congestive heart failure is associated with coronary endothelial

Another source of vascular reactive oxygen species production that has received substantial attention is endothelial nitric oxide synthase (eNOS). Nitric oxide synthase (NOS) exists in three isoforms; endothelial NOS, neuronal NOS and inducible NOS (Mayer et al., 1990; Pollock et al., 1991; Lorsbach et al., 1993). All of these enzymes convert Larginine to nitric oxide and citrulline. The first two are constitutively expressed in endothelial and neuronal tissue and produce small amounts of nitric oxide in a short time. eNOS is a cytochrome P450 reductase-like enzyme that catalyzes electron transport from the electron donor NADPH to a prosthetic heme group. The enzyme requires tetrahydrobiopterin, to transfer electrons to a guanidine nitrogen of L-arginine to form nitric oxide. In the absence of either Larginine or tetrahydrobiopterin, eNOS can produce superoxide and hydrogen peroxide. This phenomenon has been referred to as NOS uncoupling. For instance, in oxidative states, reduction in tetrahydrobiopterin results in uncoupling of eNOS (Landmesser et al., 2003) resulting in production of superoxide by the eNOS monomer. Uncoupling of eNOS in the endothelium may lead to oxidative stress and endothelial dysfunction through different mechanisms (Cheng et al., 2010).

4.3. Xanthine oxidase Xanthine oxidoreductase, a molybdoenzyme, has two interconvertible forms, xanthine dehydrogenase and xanthine oxidase. Xanthine oxidase reduces oxygen and xanthine dehydrogenase can reduce either oxygen or NAD (Waud and Rajagopalan, 1976). Both forms catalyse the conversion of hypoxanthine to xanthine and xanthine to uric acid, the end product of purine catabolism in humans (Hille and Nishino, 1995). Immunohistochemistry methods showed that xanthine oxidoreductase is located in both human endothelial (Bruder et al., 1984) and bovine capillary endothelial cells (Jarasch et al., 1981). In humans, xanthine oxidoreductase, has also been identified in liver, small intestine and mammary gland (Linder et al., 1999).

4.5. Cytochrome P450 The cytochrome P450 (CYP450) enzymes are membrane-bound, heme-containing terminal oxidases. These enzymes are responsible for the metabolic activation and/or inactivation of vitamins, steroids and the majority of cardiovascular drugs. Most CYP450s are expressed in the liver but are also present in the heart (Abraham et al., 1987) and vascular endothelial cells (Node et al., 1999). CYP450 enzymes expressed in the cardiovascular system have an important role on the regulation of vascular tone (Campbell et al., 1996; Fisslthaler et al., 1999). Moreover, some other CYP enzymes are constitutively expressed and metabolize arachidonic acid into biologically active eicosanoids such as epoxyeicosatrienoic acids (EET) and they are often described as the third pathway of arachidonic acid metabolism (in addition to cyclooxygenases and lipoxygenases). Many CYP450 isoforms are able to generate EET. EET have several vascular effects such as vasodilation (Fisslthaler et al., 1999) and antithrombotic effects (Node et al., 2001). Different CYP isoforms seem to generate varying amounts of oxygenderived free radicals (Puntarulo and Cederbaum, 1998). For example, the proapoptotic effect of CYP2E in glutathione-depleted cells has been linked to enhanced CYP450-associated oxidative stress (Nieto et al., 2001) whereas bovine aortic endothelial cells transfected with CYP2J are protected against the oxidative stress induced by hypoxia and reoxygenation (Yang et al., 2001a,b). Moreover, in coronary endothelial cells, it was reported that expression of CYP2C is not only able to generate the potent vasorelaxant EET but also is a potential source of

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reactive oxygen species within the coronary wall (Fleming et al., 2001). However, the clinical importance of CYP450-induced reactive oxygen species generation and associated cardiovascular or endothelial function is not yet fully known. 5. Reactive oxygen species generation in diabetes An increase in superoxide levels has been reported in diabetic rats (Sartoretto et al., 2007; Gryglewski et al., 1986), and in diabetic hypertensive patients (Dixon et al., 2005). Direct evidence of oxidative stress in diabetes is based on the measurement of oxidative stress markers such as nitrotyrosine (Ceriello et al., 2001; Vega-Lopez et al., 2004). Monocytes from patients with diabetes showed increase production of superoxide relative to those from normal controls (Ding et al., 2007). The role of hyperglycaemia in generating reactive oxygen species is supported by in vitro studies. Thus increased superoxide production was demonstrated in endothelial cells grown under hyperglycemic conditions (Hattori et al., 1991). Rat and human mesangial cells cultured in the presence of high glucose concentrations showed increased lipid peroxidation and also upregulation of a number of thiol antioxidant genes (glutathione peroxidase 1, peroxiredoxin 6, and thioredoxin 2); lipid peroxidation was markedly increased if the thiol antioxidant pathway was disrupted (Morrison et al., 2004). Increased lipid peroxidation and reduced antioxidant defences have been demonstrated in patients with either type 1 or type 2 diabetes (Parthiban et al., 1995; Akkus et al., 1996; Hoeldtke et al., 2009; Whiting et al., 2008). It has been hypothesised that the marked fluctuations in blood glucose seen in poorly treated diabetes, rather than hyperglycaemia per se, is responsible for the increased oxidative stress seen in diabetes (Hirsch and Brownlee, 2005; El-Osta et al., 2008). In order to design appropriate therapies it is important to understand how hyperglycaemia results in oxidative stress and how reactive oxygen species produce endothelial and other cell damage in diabetes. Hyperglycaemia increases reactive oxygen species production through direct effects of glucose and free fatty acids and through the generation of advanced glycation end products. 5.1. Direct effects of glucose and free fatty acids Direct exposure of endothelial cells to hyperglycaemic concentrations of glucose increases the formation of reactive oxygen species (Nishikawa et al., 2000; Inoguchi et al., 2000), activation of NADPH oxidase being strongly implicated (Inoguchi et al., 2000; Li and Renier, 2006). NADPH oxidase may be activated through an increased diacylglycerol mediated activation of protein kinase C (PKC) (Inoguchi et al., 2000). High concentrations of glucose were also reported to activate PKC in rat mesangial cells through an increased production of TGFβ leading to a PI3-kinase-dependent activation of PKCζ, with consequent activation of NADPH oxidase and reactive oxygen species production (Xia et al., 2008). ROS also appear to activate PKC, since antioxidants were found to reduce PKC activation in response to high glucose, so that reactive oxygen species appear to be both upstream activators and downstream mediators of PKC, creating a vicious cycle (Lee et al., 2006). Interestingly, NADPH oxidase activation was abolished in PKCβ−/− mice with diabetes and these mice were shown to be resistant to diabetes-induced renal dysfunction (Ohshiro et al., 2006). In line with the hypothesis that fluctuations in blood glucose are important in producing oxidative stress (Hirsch and Brownlee, 2005), it was shown that intermittent high glucose increased both the markers and consequences of oxidative stress in human umbilical vein endothelial cells (Quagliaro et al., 2003). Hyperglycaemia not only increases the production of reactive oxygen species but also reduces endogenous antioxidant systems. Reactive oxygen species may be reduced by thioredoxin which is normally inactivated by an endogenous inhibitor, thioredoxin-interacting protein

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(Txnip) (Nishiyama et al., 1999). This inhibitory protein was shown to be induced by hyperglycaemia (Schulze et al., 2004). Free fatty acids also stimulate ROS formation in endothelial cells (Inoguchi et al., 2000; Du et al., 2006; Li et al., 2009;Yeop Han et al., 2010) and the mechanisms appear to be similar to those mediating the effects of glucose. Thus free fatty acid-mediated ROS production was associated with PKC activation and prevented by PKC inhibitors (Inoguchi et al., 2000). 5.2. Advanced glycation end products (AGEs) AGEs, such as N-carboxymethyl lysine and pentosidine are formed as a result of non-enzymic glycation and oxidation of proteins, lipids and polynucleotides. The receptor (RAGE) for advanced glycation end products (AGE) was identified and cloned in 1992 (Neeper et al., 1992). Like Toll-like receptors, RAGE is a pattern recognition receptor that induces inflammation on activation by a number of endogenous ligands (Lin et al., 2009). In the present context, historically, the main ligands of interest are AGEs but S100/calgranulins (Hofmann et al., 1999) and HMGB1 (high mobility group protein 1; amphoterin) (Hori et al., 1995; Wang et al., 1999) from inflammatory white cells also activate RAGE. Exposure of normal human monocytes to RAGE ligands increased superoxide generation (Ding et al., 2007). Reactive oxygen species themselves increase the formation of AGEs (Anderson and Heinecke, 2003). In both vascular endothelial cells and monocytes activation of RAGE also upregulates the transcription factor NF-κB (Hofmann et al., 1999; Orlova et al., 2007), activation of which by cytokines, such as TNFα, leads to generation of reactive oxygen species (Antosiewicz et al., 2007; Picchi et al., 2006; Gauss et al., 2007; Young et al., 2008) through upregulating the expression of NADPH oxidase (Kuwano et al., 2008 ). NADPH oxidase itself also activates NF-κB (Clark and Valente, 2004; Collins-Underwood et al., 2008). Exposure of human aortic endothelial cells to high glucose concentrations increases the expression of RAGE and the RAGE ligands S100A8 and HMGB1, this effect being mediated by reactive oxygen species (Yao and Brownlee, 2010). Gao et al. (2007) showed that AGEs and NF-κB signalling play a pivotal role in elevating circulating and/or local vascular TNFα production, which then activates ROS production. Thus, a vicious cycle of reactive oxygen species generation, AGE formation, RAGE/RAGE ligand upregulation, NF-κB activation, cytokine formation, NADPH oxidase and further free radical formation is created (Fig. 1). 6. Effects of reactive oxygen species on endothelial function in diabetes Endothelial dysfunction is clearly evident in both clinical (Morcos et al., 2001; Schalkwijk and Stehouwer, 2005) and experimental (Mekinova et al., 1995; Kedziora-Kornatowska et al., 2003) diabetes. Its manifestations include impaired endothelium-dependent vasodilatation (Mayhan, 1989; Watts et al., 1996; Lekakis et al., 1997; Edgley et al., 2008) increased expression of adhesion molecules (ICAM-1 and VCAM-1) (El-Mesallamy et al., 2007), adhesion of monocytes (Yorek and Dunlap, 2002), increased platelet adhesiveness (Ferreira et al., 2006) and atherosclerosis. Reactive oxygen species may contribute to this dysfunction (Tesfamariam and Cohen, 1992; Pieper et al., 1997) in a number of ways but inactivation of endothelial nitric oxide or inhibition of nitric oxide formation are important mechanisms (Harrison, 1997; Hink et al., 2001; Bitar et al., 2005; Münzel et al., 2008). Reactive oxygen species were also shown to inhibit eNOS as well as prostacyclin synthetase (Du et al., 2006), thus offering additional mechanisms for disruption of endothelium-dependent vasodilatation. Moreover, tetrahydrobiopterin, an essential co-factor for nitric oxide synthase, is rapidly oxidized to an inactive metabolite by peroxynitrite, the product of the interaction of superoxide and nitric oxide, contributing to the inactivation of eNOS (Milstien and Katusic, 1999).

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Fig. 1. Role of hyperglycemia in endothelial dysfunction.

There is evidence that reduced bioavailability of nitric oxide is compensated early in diabetes by preserved function of EDHF (Pannirselvam et al., 2006), although the converse has also been reported i.e. an early-diabetes induced impairment of EDHF-mediated vasodilatation, which is compensated for by elevated nitric oxide production (Fitzgerald et al., 2007). Impairment of EDHF-mediated, acetylcholine induced vasodilatation was demonstrated in small resistance vessels in a rat model of type 2 diabetes (Burnham et al., 2006). EDHF-mediated vasodilation was also found to be impaired in diabetic rat mesenteric arteries (Fukao et al., 1997; Makino et al., 2000). While there is good evidence supporting the role of reactive oxygen species in the defect in endothelial derived nitric oxide in diabetes, the mechanism underlying impaired EDHF mediated responses have not been clarified. However, a role for reactive oxygen species was deduced from experiments showing that administration of the metal chelator trientene to streptozotocin-diabetic rats, significantly restored endothelium dependent vasodilatation mediated by both nitric oxide and EDHF in the rat mesenteric vascular bed (Inkster et al., 2002). A major contributor to reactive oxygen species- mediated endothelial damage is poly (ADP ribose) polymerase (PARP), also known as poly (ADP ribose) synthetase (PARS), which is a multifunctional nuclear enzyme (D'Amours et al., 1999) that is activated by DNA strand breaks. Among the PARP isoforms, PARP-1 is the best characterized; it transfers ADP ribose units from nicotinamide adenine dinucleotide (NAD+) to nuclear proteins. With moderate amounts of DNA damage, PARP-1 is thought to participate in the DNA repair process (Althaus et al., 1999). However, oxidative stress, which induces a large amount of DNA damage, can cause excessive activation of PARP-1, leading to depletion of its substrate NAD. In the course of resynthesizing NAD, ATP is also depleted, resulting in cell death as a consequence of energy loss (Oleinick and Evans, 1985; Jagtap and Szabo, 2005). PARP activation is important in several diseases (Eliasson et al., 1997; Pieper et al., 1999) including diabetes (Burkart et al., 1999; Garcia Soriano et al., 2001; Pacher and Szabo, 2005; Xu et al., 2008) and there is evidence for its role in hyperglycaemiaa-induced endothelial damage (Du et al., 2003). Clinical studies also suggest altered activity of PARP-1 in monocytes of type 2 diabetic patients and an increased expression of PARP-1 in skin biopsies of patients with type 2 diabetes (Szabo et al., 2002).

Furthermore, PARP inhibitors prevented hyperglycaemia-induced endothelial damage (Du et al., 2003) and ameliorated nephropathy in type 2 diabetic mice (Szabo et al., 2006). A further important role of reactive oxygen species in diabetesinduced endothelial dysfunction is the oxidation of low-density lipoprotein, a key player in atherosclerosis (Morel et al., 1984; Parthasarathy et al., 1986; Lamb et al., 1992; Ujihara et al., 2002). 7. Therapeutic interventions The fundamental therapeutic intervention in diabetes to reduce oxidative stress and the development of long term complications is the achievement of tight control of blood glucose from as early as possible after the diagnosis (Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) Research Group, 2009; Holman et al., 2008). This aspect will not be reviewed here. However, it is worth highlighting experimental studies that have shown oxidative stress is much more difficult to reverse by good metabolic control if the achievement of such control is delayed after the induction of diabetes (Kowluru et al., 2004). Until it is possible to readily achieve tight control of blood glucose in all patients from the time of diagnosis, adjunct therapy to reduce oxidative stress may be desirable. Several experimental studies suggest that antioxidants may reduce the development of diabetic complications. For example, treatment with either vitamin E or the antioxidant probucil prevented lipid peroxidation and renal hypertrophy in streptozotocin diabetic rats (Kim et al., 2000). Vitamin E alone prevented glomerular hyperfunction and albumin excretion in strepozotocin diabetic rats (Koya et al., 1997). Similarly, a combination of vitamins E and C administered for 12 weeks decreased lipid peroxidation and augmented the activities of antioxidant enzymes in the kidneys of stretozotocin diabetic rats; the treatment also reduced urinary albumin excretion, decreased kidney weight and reduced the thickness of the glomerular basement membrane (Kedziora-Kornatowska et al., 2003). Administration of vitamin E to diabetic mice (with a haptoglobin 2 genotype) significantly protected against diabetic nephropathy (Nakhoul et al., 2009). Tocotrienol, a component of vitamin E that may accumulate more effectively in membranes than α-tocopherol (Yoshida et al., 2007), was

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shown to ameliorate experimental nephropathy in the STZ-diabetic rat (Kuhad and Chopra, 2009). Inhibition of xanthine oxidase, an important source of reactive oxygen species, using allopurinol improved vascular and neural function in experimental STZ-induced diabetes in the rat (Inkster et al., 2007). Podocyte-specific overexpression of the antioxidant protein metallothionein reduced podocyte damage, glomerular cell death and albumin excretion and diminished the expansion of glomerular and mesangial volume in a mouse model of diabetic nephropathy (Zheng et al., 2008). Some clinical studies have also yielded promising results. A small, short-term (15-day) single blind study showed that administration of an antioxidant mixture (N-acetylcysteine, vitamin E and vitamin C) to control subjects, as well as patients with type 2 diabetes and impaired glucose tolerance reduced the elevation in oxidants and endothelial markers evoked by a fat meal (Neri et al., 2005). Another, short-term, but randomized double blind, placebo controlled study examined the effects of vitamins E and C with or without zinc and magnesium and demonstrated reduced albumin excretion, along with evidence of reduced lipid peroxidation in groups receiving the vitamins (Farvid et al., 2005). Large doses of vitamin E administered for 4 months in a double blind, placebo controlled trial improved retinal blood flow and creatinine clearance in patients with type 1 diabetes (Bursell et al., 1999). However, disappointingly, results from large, long-term clinical trials using general anti-oxidants, such as vitamin E, showed no beneficial effect (Yusuf et al., 2000; Lonn et al., 2005). These negative outcomes may not necessarily indicate that the oxidative stress hypothesis is incorrect or that antioxidants will not be useful. For example, if reactive oxygen species are produced mainly in the mitochondria, then vitamin E may not gain access to that cellular compartment, limiting its effectiveness (Green et al., 2004). Moreover, high dose vitamin E may increase all cause mortality (Miller et al., 2005), an effect possibly attributable to a paradoxical prooxidative effect (Winterbone et al., 2007). Very recently, antioxidants (a combination of vitamins C and E) were found to decrease the beneficial effects of exercise on insulin sensitivity in human subjects (Ristow et al., 2009). This was associated with prevention of exercise-induced increases in the expression of reactive oxygen species-sensitive transcriptional regulators of insulin sensitivity and reactive oxygen species defense capacity. Thus, a deeper understanding of the role of reactive oxygen species is required, as well as more knowledge of the pharmacology of antioxidant agents.

7.1. Novel approaches to antioxidant therapy The use of new antioxidant agents that penetrate specific cellular compartments may provide a new approach to dealing with oxidative stress in diabetes. Thus agents such as idebenone and mito-Q , which are selectively taken up into mitochondria should be explored (Hausse et al., 2002; Dhanasekaran et al., 2004; Green et al., 2004). Edaravone, 3methyl-1-phenyl-2-pyrazolin-5-one, is a strong, novel scavenger of free radicals (Higashi et al., 2006). It has been shown that edaravone ameliorates renal ischemia/reperfusion injury by scavenging free radicals produced in renal tubular cells and inhibiting lipid peroxidation (Doi et al., 2004). It also has preventive effects on brain injury following ischaemia and reperfusion (Higashi, 2009). Edaravone may represent a new therapeutic intervention for endothelial dysfunction induced by hyperglycemia. Mimetics of superoxide dismutase, an important antioxidant enzyme, have been investigated in experimental models of diabetes. Tempol (4-hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl) improved endothelial function in Zucker diabetic fatty rats (Belin de Chantemèle et al., 2009), streptozotocin-diabetic rats (Nassar et al., 2002; Woodman et al., 2008) and in the db/db mouse (Wong et al., 2010). In vitro pretreatment of sciatic nerve epineurial arterioles from streptozotocin-

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diabetic rats with tempol reversed the impairment of acetylcholinemediated vascular relaxation (Coppey et al., 2003). As NADPH oxidase is an important source of reactive oxygen species, targeting this enzyme may provide another approach to reducing the oxidative stress of diabetes and its consequences. Indeed, administration of the NADPH oxidase assembly inhibitor apocynin attenuated the long-term effects of streptozotocin -induced diabetes in producing albuminuria and glomerulosclerosis (Thallas-Bonke et al., 2008). Resveratrol is a polyphenol phytoalexin which can reduce vascular superoxide levels (Li and Forstermann, 2009) and restore endothelial function in type 2 diabetes by inhibiting TNFα-induced activation of NADPH oxidase and preserving eNOS phosphorylation (Zhang et al., 2009a,b). Nrf2 (NF-E2-related factor-2) is a transactivator of genes containing an antioxidant response element (ARE) in their promoter. Such genes code for a number of enzymes including NADPH:quinone oxidoreductase, glutathione S-transferases and aldo-keto reductases having an important role in the protection of cells against oxidative stress (Xue et al., 2008). Xue et al. (2008) showed that activation of Nrf2 using sulphoraphane, which increased ARE-linked gene expression, prevented hyperglycaemia-induced reactive oxygen species formation. Moreover, the biochemical consequences of increased reactive oxygen species formation, including activation of PKC and the increased cellular accumulation and excretion of the glycating agent methylglyoxal were also prevented. Taken all together, these new strategies may suggest the potential for better treatment approaches to reduce the burden of oxidative stress and to improve endothelial function in diabetes. 8. Summary Reactive oxygen and nitrogen species are generated by all aerobic organisms. Enzymes capable of generating reactive oxygen species within the vasculature are nitric oxide synthases, NADPH oxidase, xanthine oxidase, all of which are reported to be functional in endothelial cells. However, the primary biochemical source of reactive oxygen species in the vasculature, particularly of superoxide, appears to be the membrane associated NADPH oxidase enzyme complex. Although, oxidative stress has been implicated in the pathology of different diseases such as cancer, diabetes mellitus, inflammatory disease and ageing, the relative contribution of each of the potential reactive oxygen species producing enzymes to the overall reactive oxygen species production is not known. Techniques other than the pharmacological inhibition of reactive oxygen species producing enzymes are required to determine the importance of each individual enzyme in specific cell and tissue. A single cellular source of reactive oxygen species as the initiator of hyperglycemia-induced endothelial dysfunction is an attractive prospect and potentially simplifies therapeutic targets. Acknowledgments This work was supported by a grant to CBC from the Canadian Institutes of Health Research (MOP 43978).

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