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Translational Therapeutics at the Platelet Vascular Interface: A CME-Certified Activity |
From the Boston University School of Medicine, Mass.
Correspondence to Jane E. Freedman, Boston University School of Medicine, 715 Albany Street, W507, Boston, MA 02118. E-mail freedmaj{at}bu.edu
| Abstract |
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Key Words: platelet antioxidant thrombosis redox
| Introduction |
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Redox changes occur as a function of normal platelet activation; however, the introduction of additional oxidative stress in certain settings may be prothrombotic. Modulation of platelet or vascular redox status, the presence of reactive oxygen species, and the addition of exogenous antioxidants can alter platelet activation in vitro and in vivo and may have (patho)physiological ramifications.
The clinical role of oxidative stress in platelet function and thrombosis is not straightforward. Although earlier epidemiological studies found that dietary antioxidant consumption was inversely associated with the development of coronary artery disease, more recent studies of vitamin supplementation have presented conflicting or negative results.1 Interestingly, some of the negative side effects of antioxidant therapies, such as enhanced hemorrhagic stroke, may be attributed to changes in the thrombotic response. Although the effects of antioxidants were attributed to the prevention of oxidative modification of low-density lipoprotein (LDL) and the inhibition of atherogenesis, other effects may be relevant, including regulation of platelet activation, which is dependent on the balance between oxidative stress and redox state. As platelet function has also been implicated in the development of atherosclerosis and in the acute occlusion of coronary vessels,2,3 oxidative processes and platelet redox status may have far reaching effects on the homeostasis of vasculature.
| Platelet Activation, Cardiovascular Events, and the Role of Antioxidants |
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Epidemiological studies initially suggested that antioxidants play a role in the prevention of cardiovascular disease. Plasma antioxidant levels were found to inversely correlate with the development of angina,8 and dietary antioxidant consumption was inversely associated with the development of clinical coronary artery disease.9 Because oxidative processes are important in the development of atherosclerosis, the use of antioxidant supplementation was proposed for the treatment and prevention of coronary disease. However, many studies of vitamin therapy have failed to show clinical benefit.1,10
Interestingly, studies have shown that despite lack of mortality benefit, supplemental antioxidants are associated with hemorrhagic stroke, suggesting platelet inhibition.11 The precise mechanism(s) accounting for changes attributable to antioxidants in coronary disease remains unknown. Animal and cell culture data suggest that antioxidants preserve NO bioactivity in the face of oxidative stress. Because oxidative stress may alter platelet function, it is also conceivable that the effects of antioxidants may be a consequence of their enhancing or promoting the antiplatelet effects of NO derived from both endothelial cells and platelets. As discussed, the assumption that this leads to a decrease in acute coronary syndromes secondary to platelet-dependent thrombosis has not been borne out by large clinical trials.
| Reactive Oxygen Species and Platelet Function |
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Reactive oxygen species derived from both platelets and other vascular sources have been shown to alter platelet responses. Superoxide is produced by platelets,14,15 as are hydroperoxy derivatives of long-chain fatty acids (eg, 12-HpETE). Superoxide, in particular, is known to augment platelet aggregation responses.16 Low (µmol/L) concentrations of hydrogen peroxide, in the presence of plasma, inhibit platelet function.17 Although high (mmol/L) concentrations of hydrogen peroxide have been shown to stimulate platelet aggregation, the physiological relevance of levels greater than 1 mmol/L is questionable.18 Treatment of platelets with thrombin stimulates mitochondrial membrane potential depolarization and endogenous generation of hydrogen peroxide. In addition, thrombin-induced apoptosis may be mediated by endogenous generation of hydrogen peroxide in platelets.19
Platelet-dependent reactive oxygen species appear to come from several sources. Platelets activated with different agonists may produce intracellular reactive oxygen species by nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase.20 NAD(P)H oxidase is present in platelets, and the activation of platelets is known to be associated with the activation of a gp91phox-dependent enzyme.21 These studies have also shown that platelet production of reactive oxygen species enhances GP IIb/IIIa activation but not alpha or dense granule secretion.20 NAD(P)H oxidase inhibitors and superoxide scavengers also reduce platelet aggregation and thrombus formation on collagen.22 Collagen also induces NAD(P)H oxidase-dependent superoxide release in platelets, which in turn enhances availability of released ADP, resulting in increased platelet recruitment.23 Consistent with these studies, platelets from gp91phox-deficient patients produce only a small amount of reactive oxygen species.24
| Nitric Oxide, Platelet Function, and Thrombosis |
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Constitutive nitric oxide synthase (eNOS, cNOS, NOSIII) has been identified in both human platelets and megakaryoblastic cells.28 Platelet aggregation is enhanced by incubation with inhibitors of eNOS and inhibited by incubation with the eNOS substrate, L-arginine.29 Interestingly, studies report NO release from resting30 and aggregating platelets.31 Platelet NO release influences platelet recruitment to the growing thrombus,32 and impaired platelet-derived NO release is associated with acute coronary syndromes.33 Coronary risk factors are also reported to be associated with decreased platelet-derived NO levels.33 Impaired platelet NO responsiveness has also been shown to be an independent predictor of increased mortality and cardiovascular morbidity in patients with acute coronary syndromes.34 However, in animal models, deficiency of eNOS is not associated with spontaneous thrombosis.35 Interestingly, deficiency of eNOS is associated with enhanced fibrinolysis attributable to lack of NO-dependent inhibition of Weibel-Palade body release.36,37 These compensatory processes highlight the complexity of NO-dependent regulation of vascular homeostasis. Such compensatory mechanisms may partially explain the lack of spontaneous thrombosis, minimally elevated baseline blood pressure, and normal life span that are seen in animals deficient in a pivotal regulator of vascular patency.36
| Superoxide and Platelet Function |
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It is possible that NO bioactivity is dependent on platelet antioxidant status. Platelets have a number of antioxidant defenses, including superoxide dismutase (SOD). Human platelets contain approximately 1 femtogram of SOD/platelet, or about one fifth of that present in leukocytes. Approximately 77% of platelet SOD is believed to be Cu/Zn SOD, whereas the remainder is Mn SOD. SOD plays a role in normal platelet function and the prevention of thrombosis.40 Studies suggest that dismutation of superoxide decreases platelet-dependent thrombus formation by potentiation of endogenous NO bioactivity.
| Antioxidants and Platelet-Mediated Thrombosis |
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-tocopherol, and increased lipid peroxidation.41 Tocopherol oxidation in platelets can be blocked by preincubation of platelets with ascorbate.42 In
-tocopherol-depleted platelet lysates, the addition of either ascorbate or glutathione causes significant tocopherol regeneration.43 Evidence suggests that antioxidant status is an important determinant of platelet function. In normal individuals, selenium supplementation leads to increased plasma glutathione peroxidase activity and a prolongation of the bleeding time.44 Decreased human platelet antioxidant content is associated with enhanced platelet activation responses, and normal aging is associated with increased platelet aggregation.45 Smoking-induced platelet hyperactivity is associated with increased formation of lipid hydroperoxides and normalization of platelet aggregation with the addition of exogenous antioxidants.46
-Tocopherol has been shown to be a platelet inhibitor causing dose-dependent inhibition of platelet aggregation and 5-hydroxytryptamine release in response to ADP, epinephrine, and collagen.47 In men with previous coronary artery bypass graft surgery, vitamin E supplementation in the setting of colestipol-niacin treatment was associated with a reduction in coronary artery lesion progression.48 However, enthusiasm for the use of supplemental vitamin E decreased in light of other trials demonstrating no beneficial effect.10 The platelet inhibitory properties of vitamin E supplementation do not appear to be entirely irrelevant as supplementation is associated with increased hemorrhagic stroke.11
Antioxidant enzymatic mechanisms that metabolize these species also alter the prothrombotic effects of specific reactive oxygen species. One of these enzymes is glutathione peroxidase. Glutathione peroxidases are selenocysteine-containing enzymes that reduce hydrogen and lipid peroxides to their corresponding alcohols and use glutathione as an obligate cosubstrate. Hydroperoxides produced by the platelet (PGG2, 12-HpETE, and PLOOH) are metabolized by the selenium-dependent glutathione peroxidase enzyme that is also present in platelets. Glutathione peroxidase is tightly coupled to the hexose monophosphate shunt through reduced NAD(P)H which restores reduced glutathione concentrations and reestablishes the platelet thiol redox state via glutathione reductase. Glutathione depletion in platelets leads to attenuated glutathione peroxidase activity and increased lipid peroxidation. Antioxidants may indirectly inhibit platelets through the metabolism of reactive oxygen species, many of which alter platelet function. Glutathione peroxidase potentiates the inhibition of platelet function by NO by reducing LOOH.49 Impairment of this process can lead to a clinical thrombotic disorder as shown in thrombotic strokes in childhood.50
| Inflammation, Platelets, and Oxidative Stress |
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| Platelets, Oxidative Stress, and Disease |
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Platelet superoxide production in patients with hypertension alone and in patients with coexistent diabetes mellitus has been examined. It was shown that eNOS can reside in the uncoupled state in patients with hypertension and, to a greater extent, in patients with coexisting hypertension and diabetes, and that this contributes significantly to increased superoxide production in these disease states.58
| The Effect of Therapeutics on Platelet-Dependent Oxidative Stress |
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At therapeutically relevant concentrations, dipyridamole suppresses the formation of reactive oxygen species in platelets and endothelial cells and improves cellular redox status, with data suggesting that the redox-dependent properties of dipyridamole have a direct effect on vascular cells.62 In addition, dipyridamole enhances platelet inhibition by amplifying the signaling of NO donors suggesting that enhancement of endothelium-dependent NO/cGMP-mediated signaling may be a relevant component of dipyridamole effect.63
Polymeric flavonoids, such as those found in red wine and purple grapes, contain antioxidant properties believed to be protective against cardiovascular events. Extracts from grape skins or seeds alter platelet release of reactive oxygen intermediates with enhanced NO release and attenuated superoxide production. Incubation with seed or skin extracts led to an immediate attenuation of release of the inflammatory mediator, sCD40L.64 The polyphenols quercetin and catechin synergistically act in reducing platelet recruitment via inhibition of PKC-dependent NAD(P)H oxidase activation. This results in NO-mediated platelet GP IIb/IIIa downregulation.65
| Summary |
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-tocopherol, inhibit platelet aggregation, the interaction between reactive oxygen species, antioxidants, and NO may contribute to platelet aggregability and thrombus formation although not always with the anticipated clinical response. In summary, the regulation of oxidative stress as well as reactive oxygen and nitrogen species plays an important role in platelet function and thrombosis and the clinical expression of thrombotic events.
| Acknowledgments |
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Dr. Freedman received research support from Boehringer Ingelheim Pharmaceuticals.
| Footnotes |
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