Cardiovascular disease (CVD) is the leading cause of death in the industrial world (Go et al., 2013). All forms of atherosclerotic CVD (coronary artery disease, cerebral vascular disease, and peripheral artery disease) are complex in their etiology; however, risk factors common to all forms include smoking, physical inactivity, obesity, hypertension, hyperglycemia, and dyslipidemia (Go et al., 2013). Endothelial dysfunction is integral to atherogenesis and is characterized by limited bioavailability of nitric oxide (NO). Cardiovascular risk factors negatively influence the bioavailability of NO and cause endothelial dysfunction (Münzel, Sinning, Post, Warnholtz, & Schulz, 2008).
The effects of CVD risk factors are partially modulated by intricate biochemical mechanisms involving reactive oxygen and nitrogen species (RONS). Although oxygen is the substrate in the enzymatic and nonenzymatic formation of reactive oxygen species (ROS), it is essential for eukaryotic life, because most organisms use it to extract energy from organic macromolecules. Furthermore, oxygen plays a key role in the protection of cellular life as a necessary component of the immune system—particularly the neutrophil (Cascão, Rosário, & Fonseca, 2009) Because of oxygen’s ready bioavailability and ease of distribution, it is advantageous for these cellular processes; however, oxygen also can accept single electrons to form unstable derivatives (i.e., free radicals). Internally, eukaryotic organisms generate RONS via both enzymatic reactions and nonenzymatic sources that are commonly expressed in conditions such as atherosclerosis and ischemia/reperfusion injury (I/RI; Berry & Hare, 2004; McCord, 1985; Powers & Jackson, 2008). In addition, environmental factors, such as ultraviolet radiation and cigarette smoke, can promote a pro-oxidant state within the body.
Therapeutic lifestyle alterations, such as following a cardioprotective diet rich in antioxidants and phytochemicals, participating in regular aerobic exercise, and adhering to certain pharmacological therapies (if indicated), may alleviate the pro-oxidant state that is linked heavily to endothelial dysfunction. Therapeutic lifestyles may promote a low level of oxidative stress that can promote the upregulation of the endogenous antioxidant systems—a cellular process called hormesis (Gomez-Cabrera, Domenech, & Viña, 2008).
This review discusses the biochemical generation of RONS and how they pertain to dysfunction—an important precursor to CVD. Current evidence based on clinical trials of therapeutic lifestyle changes and cardioprotective pharmacological agents on oxidative stress and endothelial dysfunction are presented.
ENDOGENOUS SOURCES OF RONS
Sources of oxidative stress, links to endothelial dysfunction, and contributors to atherosclerosis are shown in Figure 1. Sources of RONS include (a) reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, (b) xanthine oxidase (XO), (c) respiring mitochondria, (d) myeloperoxidase (MPO) from within the atheroma that releases hypochlorous acid, (e) lipoxygenase and angiotensin II (AII), and (f) exogenous sources.
Reduced NADPH Oxidase
NADPH oxidase is a prevalent source of the parent-free, radical superoxide anion (O2−) that is activated primarily via inflammatory (cytokines) and vasoactive (e.g., angiotensin II or AII) factors (Valko et al., 2007). During I/RI or other types of muscle injury, myocytes and other cells produce and release proinflammatory cytokines, including interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor alpha. These proinflammatory cytokines promote chemoattraction of neutrophils to the endothelium (Weller, Isenmann, & Vestweber, 1992) and are the stimulus for upregulation of adhesion factors (selectins) on the endothelial surface required for neutrophil adhesion (Patel, Cuvelier, & Wiehler, 2002). E-selectin (endothelial) is found on activated endothelium, whereas P-selectin (platelet) and L-selectin (leukocyte) reside on the surface of platelets and neutrophils (Bevilacqua & Nelson, 1993). Upon “capturing” or “loose” binding to the endothelium, the selectins, primarily P-selectin, mediate neutrophil rolling necessary for activation of NADPH oxidase (Zarbock & Ley, 2009). Firm adhesion to the endothelium is mediated by E-selectin, intracellular adhesion molecule-1, and vascular cellular adhesion molecule-1, acting together within integrins, and the CD11/CD18 complex on the neutrophils (Kakkar & Lefer, 2004)—with the latter being upregulated by P-selectin and platelet-activating factor. Once the neutrophil adheres to the endothelium, the activated neutrophil transmigrates through the endothelium and into the source of activation (area of inflammation and infection; Kakkar & Lefer, 2004). At the site of inflammation, activated neutrophils undergo a respiratory burst (an autoimmune response characterized by rapid release of ROS; primarily O2− and oxidants such as MPO) designed to rid the area of cellular damage and debris. The O2− generation from respiratory bursts promotes further neutrophil attraction, resulting in a positive feedback loop, characterized by oxidative stress-induced cellular damage (Petrone, English, Wong, & McCord, 1980). In addition to the plausible biological mechanisms linking NADPH oxidase with atherosclerosis, NADPH oxidase overactivity has been linked with atherosclerosis (Fortuño et al., 2006; Yusof, Miles, & Calder, 2008).
Xanthine dehydrogenase and XO are two isoforms of xanthine oxidoreductase; xanthine dehydrogenase is implemented in oxidative stress (Berry & Hare, 2004)—particularly with coronary artery disease. These isoforms are primarily known for their roles in purine metabolism, with uric acid as the end product. During ischemia, oxygen deprivation leads to the initiation of anaerobic glycolysis, resulting in lactate production and acidosis. Inefficiency of glycolysis to maintain ATP production causes ATP levels to fall and adenine nucleotides to be catabolized into adenosine, inosine, and hypoxanthine (McCord, 1985). Buildup of these metabolites is primarily because of an ischemic environment (that prevents the necessary oxidative phosphorylation needed to replenish myocyte ATP levels). Simultaneously, the ischemic environment also promotes a protease-induced transformation of xanthine oxidoreductase from dehydrogenase to oxidase form, and upon reperfusion, the necessary substrate for XO, oxygen, returns and leads to the rapid generation of O2− (McCord & Fridovich, 1968). Microvascular alterations caused by I/RI, including impairment of endothelial-dependent vasodilation in arterioles, are similar to those resulting from the well-known CVD risk factors, including dyslipidemia, hypertension, and hyperglycemia (Battelli, Bolognesi, & Polito, 2014).
During the process of cellular metabolism, electrons from reduced nicotinamide adenine dinucleotide and flavin adenine dinucleotide—produced in various steps of glycolysis, beta oxidation, and the Krebs citric acid cycle—are transported to the electron transport chain (ETC). Electrons travel along the respiratory chain, transferring electrons from complex to complex and establishing proton gradients at the enzyme complexes I, III, and IV powering complex V (ATP synthase), resulting in the production of ATP (oxidative phosphorylation). Throughout the process of oxidative phosphorylation, oxygen is utilized as the final electron receptor of electrons in the ETC in a reaction that culminates in the reduction of oxygen to water (McKee & McKee, 2009).
However, this is an imperfect process because the electron chain is “leaky.” Leakiness results in loss of electrons into the matrix and potentially in the cytosol of the cell, causing a decrease in energy production and also leading to reduction of oxygen into ROS, including O2−. It is estimated that, at rest, 90% of ROS occurs due to the escape of electrons from the ETC and that 1%–4% of oxygen is reduced to O2− during oxidative phosphorylation (Richter, 1988). In addition, during ischemia, the moderate ROS generation of O2− is most likely from a mitochondrial source (Valko et al., 2007). The general consensus is that complexes I and III are primary sites of electron leakage and generation of the ROS involved in healthy aging, whereas complex IV also may be involved in the etiology of atherosclerotic and other diseases (Pipinos et al., 2006).
MPO (From Within the Atheroma)—Releases Hypochlorous Acid
MPO is a peroxidase enzyme expressed within the neutrophil granulocyte that secretes a number of oxidants. Production of hypochlorous acid and hydrogen peroxide (H2O2) directly contributes to lipid peroxidation and posttranslational modifications of proteins (Nicholls & Hazen, 2005). MPO is expressed within the atheroma and may directly promote atherogenesis (Podrez, Abu-Soud, & Hazen, 2000). MPO appears to be directly involved in the etiology of atherosclerosis through several mechanisms, including oxidation of low-density lipoprotein, promotion of endothelial dysfunction, and development of vulnerable plaques—as reviewed by Nicholls and Hazen (2005).
Lipoxygenase and AII
AII is the principal product of the renin–angiotensin–aldosterone system and is recognized primarily for its promotion of vasoconstriction and peripheral vascular resistance. In addition, AII is responsible for maintenance of salt and water homeostasis and vascular remodeling through aldosterone secretion and angiogenic mechanisms. AII is strongly implicated in the development of hypertension and promotion of a proinflammatory and pro-oxidant state leading to the formation of free radicals, such as O2−, H2O2, and hydroxyl radicals (OH−; Griendling & Alexander, 1997). In vascular smooth muscle and endothelial cells, it is well known that AII activates NADPH oxidase to generate ROS (Hitomi, Kiyomoto, & Nishiyama, 2007); however, their production may be further mediated by multiple enzymatic sources (Püntmann, Hussain, Mayr, Xu, & Singer, 2005).
Exogenous Sources of RONS
Exogenous RONS result from air and water pollution, cigarette smoke, alcohol, heavy or transition metals, certain drugs (e.g.,cyclosporine, tacrolimus, gentamycin, bleomycin), industrial solvents, cooking (e.g., smoked meat, used oil, fat), radiation, and oxygen toxicity. Once inside the body, these exogenous compounds are decomposed or metabolized into free radicals (Pham-Huy, He, & Pham-Huy, 2008).
RONS CASCADE AND ANTIOXIDANT SYSTEMS
Figure 2 shows the RONS cascade and antioxidant systems. Oxidative stress reflects an imbalance between ROS and the antioxidant defense system, with disturbances to the redox state of cells leading to damage to proteins, lipids, and DNA with subsequent endothelial dysfunction and development of atherosclerosis.
Superoxide Anion (O2−)
The “primary” ROS (O2−) is a product of uncoupled electron transport and other enzymatic reactions within the cell. Because of the relatively long half-life—which optimizes diffusion capabilities within the cell—O2− has a number of potential targets of oxidative damage and is, therefore, implicated in the pathophysiology of several diseases (Powers & Jackson, 2008).The damaging reactions include—but are not limited to—mitochondrial DNA (Brass, Wang, & Hiatt, 2000), NO (via formation of ONOO−; Förstermann & Münzel, 2006), and peroxidation of polyunsaturated fatty acids found in cell membranes (McCord, 1985).
Hydrogen Peroxide (H2O2)
In healthy populations, most of the O2− produced during cellular respiration is dismutated into the “secondary” ROS H2O2. The antioxidant enzyme that dismutates O2− into H2O2 is superoxide dismutase (SOD; Weisiger & Fridovich, 1973). Several isoforms of SOD exist; manganese SOD (MnSOD) is found in the inner membrane space in the mitochondria, whereas copper- and zinc-containing superoxide dismutase (Cu/ZnSOD) is located in the cytosol (Okado-Matsumoto & Fridovich, 2001). The MnSOD is important in the dismutated O2− produced by the mitochondria, whereas O2− produced during enzymatic (NADPH oxidase, XO, LOO) release in the cytosol is dismutated by Cu/ZnSOD (Fukai & Ushio-Fukai, 2011). It should be noted that dismutation (or disproportionation) refers to a specific type of redox reaction in which a species is simultaneously reduced and oxidized to form two different products.
Because H2O2 does not have any unpaired electrons, it is technically not a free radical but is still considered a ROS because it is able to cross the mitochondrial membranes and enter the cytosol. In the cytosol—in the presence of a transition metal (primarily iron)—it is able to form the highly reactive ROS hydroxyl ion (OH·); this is known as the Fenton reaction. H2O2 in the presence of chloride and MPO can be converted to hypochlorous acid, an ROS that can be particularly damaging to cellular proteins (Powers & Jackson, 2008). The antioxidant-induced catabolism of H2O2 is performed primarily by enzyme glutathione peroxidase (GPx). GPx, in conjunction with reduced glutathione (GSH), converts H2O2 yielding water and oxidized glutathione (GSSH; Chance, Sies, & Boveris, 1979). GSSH is converted back to its reduced form (GSH) by glutathione reductase and the addition of substrate NADPH generated in the pentose phosphate pathway (Meister & Anderson, 1983). In the cytosol, H2O2 can also be reduced by catalase to water and oxygen (Camello-Almaraz, Gomez-Pinilla, Pozo, & Camello, 2006; Chance et al., 1979).
Hydroxyl Ion (OH·)
OH· is generally considered the most reactive of the ROS because it reacts with whichever biomolecules it collides with. Phospholipids in cell membranes and proteins are generally attacked by OH·—with the former resulting in a radical chain reaction. The process of radical chain reactions can be particularly damaging to cell membranes. Lipid peroxidation—largely accredited to OH· (Halliwell, 1989)—is initiated by OH· scavenging a hydrogen atom from an unsaturated fatty acid component of phospholipids. This reaction alters the cell membrane structure and rigidity, which results in the loss of semipermeability and culminates in cell dysfunction and cell death (McKee & McKee, 2009).
Nitric Oxide as a Reactive Nitrogen Species
Reactive nitrogen species (RNS) consist primarily of NO and ONOO−. The presence of NO promotes a vasoprotective environment, but it can also act as a weak-reducing agent by its reduction to nitric dioxide. More importantly, NO can act as a scavenger of O2− to form ONOO− (Halliwell, 1994)—another free radical that can elicit cellular damage. NO reacts with superoxide anion faster (three times as fast) than the dismutation of superoxide anion by SOD to form hydrogen peroxide (Powers & Jackson, 2008). Furthermore, the continuous formation of ONOO− can be detrimental to NO generation, as this process is implicated in the development of eNOS uncoupling—a major step in the development of endothelial dysfunction (Förstermann & Münzel, 2006). Uncoupled eNOS refers to the oxidation of eNOS cofactor tetrahydrobiopterin (BH4) by O2− or peroxynitrite (ONOO−), which results in the production of O2− from eNOS to a greater extent than that of NO and, therefore, causing oxidative stress (Förstermann & Münzel, 2006).
In addition, chronic production of ONOO− can have serious consequences that lead to the development of endothelial dysfunction. Although ONOO− has been implicated in the oxidation of DNA and lipids (Beckman & Koppenol, 1996), this RNS also has direct effects on the dilatory capabilities of the artery. Chronic ONOO− formation can lead to endothelial dysfunction via several mechanisms on BH4 and eNOS. BH4 is essential for eNOS functioning as it stabilizes the enzyme and increases the affinity of eNOS to the substrate l-arginine. ONOO− has been shown to directly oxidize BH4 to the non-eNOS cofactor BH2 (Milstien & Katusic, 1999). Without this cofactor in its reduced form, NO production is extremely limited, and the uncoupling of eNOS ensues (Laursen et al., 2001). Moreover, Zou, Shi, and Cohen (2002) have shown that RNS directly oxidize the zinc–thiolase clusters present in the eNOS enzyme. The uncoupled eNOS will now generate O2− rather than NO, leading to a twofold problem of increased oxidative stress to the cell and the exacerbation of the NO deficiency.
ONOO− not only affects the endothelium but also has damaging consequences in the vascular smooth muscle (Bassil, Li, & Anand-Srivastava, 2008). In the healthy endothelium, NO is released and binds to the smooth muscle surrounding the blood vessel, activating guanylate cyclase (GC), and through signal transduction, inhibiting the release of calcium into the cytosol, thereby promoting smooth muscle cell relaxation and vasodilation (Förstermann, Mülsch, Böhme, & Busse, 1986). GC is inhibited by ONOO−, which leads to a disruption in the signal transduction pathway where the relaxation message carried by NO is not received by the smooth muscle (Bassil et al., 2008).
In addition to its inactivation of eNOS, ONOO− is a radical that is very capable in damaging the cell structures. Similar to the OH−, ONOO− may initiate lipid peroxidation that is devastating to the endothelial membrane through an event known as arachadonic acid cascade, characterized by the acute formation of eicosanoids (Cooke, 2000). It is believed that ischemia, ONOO−, and OH− are potent activators of phospholipase A2 (PLA2)—an enzyme that cleaves arachadonic acid from the cell membrane, which initiates the release of arachadonic acid from the membrane (Samuelsson, 1987). Arachadonic acid can be metabolized by several enzymes—most notably prostaglandin endoperoxidase cyclase or COX and LOO—which, as previously mentioned, are two more contributors to O2− production. The COX and LOO reactions yield eicosanoids (prostacyclins, prostaglandins, thromboxanes, and leukotrienes), which have various effects on the vasculature. Most notably, TXA2 and leukotriene C4 (LTC4) contract smooth muscle—TXA2 further induces platelets to adhere to one another in an event referred to as platelet aggregation. These arachadonic acid metabolites contribute to the inflammatory state induced by ischemia by increasing capillary permeability, leukocyte infiltration, and the production of RONS during their synthesis via LOO and COX. A summary of the physiological mechanisms, by which RONS influence endothelial dysfunction, are presented in Table 1.
VASCULAR ENDOTHELIUM AND RONS IN THE PATHOGENESIS OF ENDOTHELIAL DYSFUNCTION
The vascular endothelium is the inner layer of cells that line the blood vessels of the circulatory and lymphatic systems. As key regulators of blood flow, endothelial cells play a major role in vascular biology via autocrine, paracrine, and hormonal-like mechanisms involving control of endothelial-derived relaxing factors (EDRF) NO and prostacyclin (PGI2) and the vasoconstrictors endothelin (ET-1) and thromboxane (TXA2). In addition to control of vasodilation and vasoconstriction, endothelial cells are major regulators of vascular homeostasis through the following mechanisms: maintenance of vascular tone, prevention of vascular smooth muscle proliferation; reduction in leukocyte adhesion and activation, inhibition of platelet aggregation, and thrombus formation (Brevetti, Schiano, & Chiariello, 2008). Alterations in these mechanisms are implicated in the development and evolution of plaques that ultimately initiate symptomatic atherosclerotic disease and its progression and may be caused by chronic inflammation and oxidative stress.
In healthy endothelium, the amino acid l-arginine and cofactor BH4 are converted to NO and l-citrulline in a reaction catalyzed by eNOS (Ignarro, Buga, Wood, Byrns, & Chaudhuri, 1987) in response to receptor agonists, such as bradykinin, adenosine, acetylcholine, or physiological stimuli such as laminar shear stress (Fleming & Busse, 2003). The resulting NO diffuses to adjacent smooth muscle cells where it promotes the G-protein-mediated activation of a membrane-bound GC (Förstermann et al., 1986) and the formation of second messenger cyclic guanosine monophosphate (cGMP; Murad, 1999)—with subsequent activation of a cGMP-dependent protein kinase (Murad, 1999). The activation of cGMP and protein kinase promotes opening of calcium-dependent potassium channels, thereby inducing a state of membrane hyperpolarization in the smooth muscle cell and inhibition of cytosolic calcium influx and reuptake of calcium into the sarcoplasmic reticulum. Regulation of calcium is, therefore, essential to maintenance of vascular tone and contractile activity in smooth muscle.
Endothelial dysfunction is considered an initial component of the pathophysiology of CVD and is associated with disease severity. Endothelial dysfunction is characterized by a decrease in production and bioavailability of NO by the endothelium that predisposes the artery to conditions of vasoconstriction and thrombosis (Coutinho, Rooke, & Kullo, 2011). Reduction in bioavailability of NO with endothelial dysfunction cannot be attributed to one single factor; in fact, it may be because of several contributing factors (Brevetti et al., 2008), such as decreased eNOS expression, insufficient l-arginine (Tousoulis et al., 2002) or BH4 (Alp & Channon, 2004), presence of eNOS antagonists such as ADMA (Böger & Bode-Böger, 2000), and increased degradation of NO (Münzel et al., 2008). Other potential factors that may affect NO bioavailability include decreased DDAH (Murray-Rust et al., 2001), increased arginase (Ming et al., 2004), and uncoupling of eNOS and GC (Bassil et al., 2008). Münzel et al. (2008) stated that endothelial dysfunction is largely because of an increased production of ROS such as O2−, which leads to reduction in vascular bioavailability of NO. Support to this claim was provided by Ohara, Peterson, & Harrison (1993), who concluded that, in pathogenic conditions, the vascular endothelium is a potent source of O2− that can inactivate eNOS. RONS appear to play a major role in cellular maladaptations, such as the inhibition of DDAH and uncoupling of eNOS, GC, and BH4, which suggests that RONS may be considered a major contributor to endothelial dysfunction (Bassil et al., 2008; Förstermann & Münzel, 2006).
THERAPIES TO ALLEVIATE OXIDATIVE STRESS AND ENDOTHELIAL DYSFUNCTION
Findings from basic biological research about RONS and endothelial dysfunction serve as the rational basis for development of prevention and treatment interventions for atherosclerotic vascular disease. Some recent trials using exercise, antioxidant supplementation, and pharmacological approaches are summarized in Table 2, and select ongoing trials are listed in Table 3.
Aerobic exercise training has had favorable effects on reduction of several modifiable, biological CVD risk factors, including hypertension (Cornelissen & Smart, 2013), hyperglycemia (Sanz, Gautier, & Hanaire, 2010), and dyslipidemia (Leon & Bronas, 2009). In accordance with these findings, aerobic exercise training appears to positively modify endothelial functioning likely via increase in bioavailability of NO. This aerobic exercise-induced increase in NO bioavailabilty is likely mediated by concurrent upregulation of endogenous antioxidant enzymes (Gomez-Cabrera et al., 2008).
It is well established that aerobic exercise training positively modulates endothelial functioning in both healthy persons and persons with diagnosed endothelial dysfunction (Beck, Casey, Martin, Emerson, & Braith, 2013; Hambrecht et al., 1998); however, the exact cellular mechanisms leading to this vasoactive benefit remain to be fully elucidated. Although less established aerobic exercise has also been shown to significantly lower both local and systemic biomarkers of oxidative stress in various clinical trials involving a wide variety of study participants, including those with congestive heart failure (Linke et al., 2005), obesity (Samjoo, Safdar, Hamadeh, Raha, & Tarnopolsky, 2013), and type 2 diabetes (de Oliveira et al., 2012). In general agreement with the reduction in oxidative stress, trials have also found an increase in endogenous antioxidant enzymes, such as SOD, GPx, and catalase (Linke et al., 2005). In addition, positive correlations exist in regards to the aerobic exercise-induced upregulation of endogenous antioxidant enzymes and subsequent elevation in NO bioavailabilty.
Although there appears to be good support to the viewpoint that aerobic exercise is an antioxidant and is a likely mediator in the positive effects on endothelial functioning, the optimal aerobic exercise prescription (dose) has yet to be determined by clinical trials. In general, clinical trials evaluating the antioxidant effects of exercise have used 12-week programs consisting of a frequency of 3 days per week and durations of 30 minutes per session at moderate intensity (3–6 METS). Therefore, it is likely that participating in an aerobic exercise regime based on current ACSM aerobic exercise recommendations, for both healthy and diseased populations (Garber et al., 2011), will exceed typical dosages of exercise used in clinical trials. Participation in such exercise programs will result in a strong potential to upregulate endogenous antioxidant enzymes, reduce local and systemic oxidative stress, and positively modulate endothelial function and NO bioavailability.
The exogenous antioxidant molecules alpha tocopherol (vitamin E), ascorbic acid (vitamin C), and beta-carotenes help prevent OH-induced cell membrane damage (Beyer, 1994). Vitamin E (especially alpha tocopherol) is a lipid-soluble vitamin, which is in proximity to the polyunsaturated fatty acids of the phospholipids in the cell membrane, scavenges OH·, thereby preventing the lipid peroxidation cascade (Burton, Joyce, & Ingold, 1983). Ascorbic acid (vitamin C), although not lipid soluble, can also protect OH·-induced cell membrane damage by two mechanisms by (a) reacting with peroxide radicals produced in lipid chain reaction before they reach the cell membrane and (b) enhancing overall antioxidant activity of vitamin E by regenerating reduced alpha tocopherol (Beyer, 1994). Therefore, a clear and plausible biological mechanism exists in regards to the ability of exogenous antioxidants to lower oxidative stress.
Dietary intakes of fruits, vegetables, deep water fatty fish (e.g., salmon), and supplements are rich sources of exogenous antioxidant compounds, including vitamins A, C, E, alpha lipoic acid, resveratrol, coenzyme Q-10, omega 3 essential fatty acids, mineral cofactors (e.g., zinc and selenium), and numerous phytochemicals. However, not all have been evaluated in clinical trials pertaining to alleviation of oxidative stress and endothelial dysfunction. To date, most clinical trials investigating the effects of supplementation on oxidative stress and endothelial dysfunction have focused on the traditional exogenous antioxidants vitamins C and E. As with aerobic exercise training, antioxidant therapies utilizing vitamins C and E have been shown in clinical trials to reduce systemic biomarkers of oxidative stress in both healthy adults (Mah et al., 2013) and patients with preexisting vascular diseases (Abdollahzad et al., 2009). In addition, administration of vitamins C and E has been shown in some (Skyrme-Jones, O’Brien, Berry, & Meredith, 2000) but not all studies (McKechnie, Rubenfire, & Mosca, 2002; Title, Cummings, Giddens, Genest, & Nassar, 2000) to acutely improve flow-mediated dilation (FMD) in patients with preexisting endothelial dysfunction. Although therapeutic use of vitamins C and E has reduced oxidative stress in patients with diagnosed CVDs, long-term effects on mortalities have yet to be shown. Classic epidemiological studies have not shown that vitamin E supplementation results in reduction of risk of CHD or mortality (in patients with previously existing CHD; Gaziano, 2004). Because of the lack of consistent randomized controlled trial evidence regarding antioxidant supplementation alleviating endothelial dysfunction and CVD risk factors paired with the failure of epidemiological studies to show reduced mortality (in patients taking antioxidant supplements), antioxidant supplementation is not supported by the American Heart Association for primary or secondary prevention of atherosclerotic CVDs. Nevertheless, dietary patterns such as the Dietary Approaches to Stop Hypertension and the Mediterranean Diet—which both include an abundance of antioxidant-containing foods (fruits and vegetables)—are recommended by the American Heart Association as “cardioprotective diets” (Mozaffarian, Appel, & Van Horn, 2011).
Current evidence supports a link between NADPH oxidase and XO-mediated oxidative stress and atherosclerosis. Several clinical trials have been performed with a goal of enzyme inhibition and a reduction of atherogenesis. The association between uric acid levels (an indicator of upregulated activity of XO) and CVD has been observed for several decades (Doehner & Landmesser, 2011), prompting consideration of therapeutic use of XO inhibitors such as allopurinol and oxypurinol. A recent meta-analysis by Higgins et al. (2012) aimed to determine the effects of XO inhibition on surrogate markers of CVD and vascular function and concluded that XO inhibition improves endothelial function and circulating markers of oxidative stress in patients with, or at risk of developing, CVD. However, clinical relevance of these findings will not be fully understood until large prospective studies examining hard-end points are available. This is an area of intense pharmacological research; a variety of XO inhibitors (and other pharmaceutical agents) is in various stages of clinical trials to determine effectiveness in alleviating or preventing atherosclerosis.
Additional pharmaceutical agents, including HMG-CoA reductase inhibitors (i.e., statins) and angiotensin-converting enzyme inhibitors (ACE inhibitors), exert multiple pleiotropic effects that have been documented to alleviate oxidative stress. Clinical trials investigating statin drugs, particularly atorvostatin and fluvastatin, have shown a reduction in circulating plasma lipid hydroperoxides, antibodies against low-density lipoprotein oxidation, and thiobarbituric acid reactive substances (TBARS) while concurrently improving vascular endothelium functioning (Murrow et al., 2012; Yoshida et al., 2010). However, in the absence of dyslipidemia, the usefulness of statins for the reduction of oxidative stress and improvement of FMD is controversial (Schneider, Schmidt, John, & Schmieder, 2011).
ACE inhibitors and angiotensin receptor blockers (ARBs), commonly prescribed for the treatment of hypertension, also exert pleiotropic cardioprotective effects, but their ability to alter oxidative stress is not as well understood in comparison to statin therapy. Recent trials investigating ACE inhibitors (Cacciatore et al., 2011; Napoli et al., 2008) and ARBs (Takiguchi et al., 2011) have shown lowered plasma and urinary isoprostane concentrations in patients with hypertension. In addition to antioxidant effects, ACE inhibitors and ARBs appear to positively modulate endothelial-dependent vasodilation (Takiguchi et al., 2011; Versari et al., 2009). Furthermore, positive correlations between changes in FMD and those in extracellular SOD have been shown, suggesting relevance to the antioxidant effects of ACE inhibitors and ARBs (Takiguchi et al., 2011). It is well established that ACE inhibitors reduce the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients (Bertrand, 2004), and this could be a result of pleiotropic effects, including the reduction in oxidative stress and enhanced endothelial functioning.
APPLICATION OF RONS AND ANTIOXIDANT REDOX BIOLOGY IN NURSING THERAPY
A strong knowledge base of redox biology, oxidative stress, and antioxidant defense systems is important for practicing nurses and nursing scientists. Primary prevention to minimize an overproduction of RONS and increase antioxidant availability should include therapeutic lifestyle changes (e.g., exercise, a prudent diet that incorporates fruits and vegetables, moderation of alcohol consumption, smoking cessation, and minimal exposures to air pollutants and gasoline fumes). Current evidence does not support specific antioxidant supplementation in primary prevention. Several therapies currently utilized in critical care nursing are based upon the concepts of redox biology discussed within this article. These therapies include vitamin C infusion for cancer treatment and ischemic pre- and postconditioning for the prevention of extensive necrosis because of I/RI, which occurs during the restoration of blood flow to a patient suffering from an acute cardiovascular event or following induced cold/ hypoxia during cardiac bypass.
Vitamin C at concentrations above 1,000 μmol/L is known to be toxic to some cancer cells but not to normal cells in vitro. This level of vitamin C can only be achieved by intravenous administration of 50–100 g and requires a trained professional for administration (Padayatty et al., 2006). Intravenous vitamin C administration decreases the GSH/GSSG ratio by inducing the oxidation of GSH—leading to the accumulation H2O2 (Park, 2013). In high concentrations, H2O2 damages the DNA and mitochondria of cancer cells, shuts down their energy supply, and leads to apoptosis—without the damage to healthy cells.
The biology of oxidative stress is also relevant to clinical management of myocardial I/RI. The pathophysiology of I/RI is multifaceted but includes acidic pH and intracellular calcium overload (in addition to oxidative stress) that contribute to necrosis (Hausenloy & Yellon, 2013). Mechanical and pharmacological therapies are aimed at reducing oxidative stress and intracellular calcium overload. Mechanical therapies include ischemic postconditioning, remote ischemic conditioning, and therapeutic hypothermia; pharmacological treatments (prior to reperfusion) include antioxidant infusion and medications to preserve mitochondrial functioning and salvage the kinase prosurvival pathway (Hausenloy & Yellon, 2013).
Therapeutic hypothermia is typically induced by the insertion of cooling catheters into a femoral vein. Cooled saline solution is circulated through either a metal-coated tube or a balloon in the catheter. The saline cools the patient’s whole body by lowering the temperature of a patient’s blood at a rate of 1.5–2°C per hour (Hinz et al., 2007). Therapeutic hypothermia can be beneficial during ischemia (by slowing tissue metabolism and pH drop) and the reperfusion phase by decreasing the amounts of RONS produced enzymatically (via the effects of temperature on enzyme kinetics; Polderman, 2004).
Remote ischemic preconditioning involves inflating a blood pressure cuff placed on the upper arm or leg to induce three or four 5-minute cycles of ischemia. Remote ischemic preconditioning has been reported to be beneficial in a variety of cardiac scenarios, including cardiac surgery, during percutaneous coronary intervention, and acute myocardial infarction (Lim & Hausenloy, 2012).This form of ischemic preconditioning has been shown to reduce lipid peroxidation, increase endogenous antioxidant enzyme expression, and downregulate ROS producing enzymes. However, further research is clearly needed in this area (Sedaghat et al., 2013).
Ischemic postconditioning involves application of brief intermittent episodes of reflow (reoxygenation) and reocclusion (ischemia, hypoxia) at the immediate onset of reperfusion and has been utilized in an effort to minimize I/RI. Several protocols may be utilized (Skyschally et al., 2009; Zhao, 2009). Ischemic postconditioning likely reduces the oxidant burden and consequent oxidant-induced injury, mediated primarily by XO and secondly attenuates the local inflammatory response to reperfusion that can also upregulate ROS-producing enzymes, such as XO and NADPH oxidase (Vinten-Johansen, Zhao, Jiang, & Zatta, 2005).
Protection against reperfusion injury in end organs (e.g., myocardium, renal, brain, liver, and organ transplantation) using SOD and CAT infusion, various XO inhibitors (e.g. allopurinol), iron chelation therapy, and pharmaceuticals, such as statin drugs, ACE inhibitors, and beta-adrenergic blocking agents (discussed above), has been successful. There has been some evidence for a beneficial use of N-acetylcysteine (currently used to treat acetaminophen toxicity and protect hepatocytes) in sepsis and various inflammatory diseases (e.g., acute respiratory distress syndrome, COPD, HIV). Organ preservation is also using solutions that contain several antioxidants (e.g., University of Wisconsin solution [UW, “gold-standard”] and the Carolina rinse solution; Scheibmeir et al., 2005). Although these antioxidant therapies are promising, much additional research is needed and practicing nurses should be well aware of current practice guidelines in this area.
A large body of research suggests that a chronic, high level of systemic oxidative stress is a primary contributor to endothelial dysfunction—a precursor to CVD development. RONS can arise from enzymatic and nonenzymatic sources and can be particularly damaging to lipids, proteins, and DNA. Endogenous antioxidant enzymes and exogenous vitamins and phytochemicals protect cells from oxidative damage. Clinical trials involving regular aerobic exercise of moderate intensity and cardioprotective dietary patterns rich in antioxidants and phytochemicals showed reductions in systemic levels of markers of oxidative stress, but via different biological mechanisms. Participation in moderate intensity aerobic exercise training results in upregulation of endogenous antioxidant enzymes, whereas adherence to a cardioprotective diet directly supports the antioxidant capacity of the body. In addition, patients with preexisting CVD risk factors—such as dyslipidemia and hypertension, who adhere to prescribed statins, ACE inhibitors, or ARBs—will likely suppress systemic oxidative stress. Although biologically plausible, it is currently unknown whether alleviation of oxidative stress directly reduces the occurrence of CVD or the resulting morbidity and mortality associated with CVD.
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