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Role of oxidative stress on platelet hyperreactivity during aging
Life Sciences 148 (2016) 17–23
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Review article
Role of oxidative stress on platelet hyperreactivity during aging Eduardo Fuentes ⁎, Iván Palomo ⁎ a Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca, Chile b Centro de Estudios en Alimentos Procesados (CEAP), CONICYT-Regional, Gore Maule R09I2001, Chile
a r t i c l e
i n f o
Article history: Received 17 October 2015 Received in revised form 3 February 2016 Accepted 8 February 2016 Available online 9 February 2016 Keywords: Aging Oxidative stress Nitric oxide Platelet activation Thrombosis
a b s t r a c t Thrombotic events are common causes of morbidity and mortality in the elderly. Age-accelerated vascular injury is commonly considered to result from increased oxidative stress. There is abundant evidence that oxidative stress regulate several components of thrombotic processes, including platelet activation. Thus oxidative stress can trigger platelet hyperreactivity by decreasing nitric oxide bioavailability. Therefore oxidative stress measurement may help in the early identification of asymptomatic subjects at risk of thrombosis. In addition, oxidative stress inhibitors and platelet-derived nitric oxide may represent a novel anti-aggregation/-activation approach. In this article the relative contribution of oxidative stress and platelet activation in aging is explored. © 2016 Elsevier Inc. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 2. Aging and cardiovascular diseases . . . . . . . . . . . . . . 3. Nitric oxide pathway and platelet inhibition . . . . . . . . . . 4. Antiplatelet activity of natural products via nitric oxide pathway 5. Aging and oxidative stress . . . . . . . . . . . . . . . . . . 6. Platelet hyperreactivity and oxidative stress status . . . . . . . 7. Clinical significance . . . . . . . . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Cardiovascular diseases (CVD) increase in incidence in the elderly, a tendency dependent on the age-related changes in vascular and hemostatic systems [1]. Age-accelerated vascular injury is commonly considered to result from increased oxidative stress [2]. In these conditions, aging is associated with immunosenescence and accompanied by a chronic inflammatory state which contributes to metabolic syndrome, diabetes and their cardiovascular consequences [3–5]. Age is a ⁎ Corresponding authors at: Immunology and Haematology Laboratory, Faculty of Health Sciences, Universidad de Talca, Casilla: 747, Talca, Chile. E-mail addresses: [email protected] (E. Fuentes), [email protected] (I. Palomo).
http://dx.doi.org/10.1016/j.lfs.2016.02.026 0024-3205/© 2016 Elsevier Inc. All rights reserved.
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nonmodifiable risk factor for atherosclerosis. Older animals develop more extensive atherosclerosis than younger animals when both groups are fed an atherogenic diet [6, 7]. Platelets have a dynamic functional repertoire that mediates haemostatic function [8]. However, platelet function is altered in older adults [9–11]. Therefore in aging, the correlation between platelet aggregation in whole blood and platelet-arterial wall interactions (in vitro and in vivo) may contribute to CVD [12]. Nitric oxide (NO) in human is produced from L-arginine by three enzymes called nitric oxide synthases (NOS): inducible (iNOS), neuronal (nNOS) and endothelial (eNOS), which differ in their dependence on Ca2+, as well as in their expression and activities. The eNOS and iNOS have been crucial in cardiovascular protection [13, 14].
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The NO is present in platelets and regulates their platelet function [15, 16]. NO stimulates cyclic guanosine monophosphate (cGMP) synthesis by activating soluble guanylyl cyclase (sGC), which plays a crucial role in preventing platelet activation [17, 18]. However, metabolic abnormalities as a result of aging cause platelet hyperaggregability involving enhanced intraplatelet reactive oxygen species (ROS) production and decreased NO bioavailability [19, 20]. NO is a reactive free radical that can participate in several types of redox reactions, some that mediated its biological effects and others that limit its activity. Inactivation of NO occurs largely through oxidative reactions mediated by ROS [21, 22]. Increased generation of ROS is found in a variety of vascular disorders and during aging [23–26]. The nitric oxide pathway plays an important role in the inhibition of platelet activation and thrombus formation. Yet, the role of oxidative stress on platelet function and thrombus risk during aging yet to be fully elucidated. In this article the relative contribution of oxidative stress and platelet hyperreactivity during aging is explored.
2. Aging and cardiovascular diseases Most studies of older populations in developed countries show a decrease in the prevalence of disabilities, and an increase in chronic diseases over the past decades [27, 28]. The world population is rapidly aging. Between 2000 and 2050, the proportion of the world's population over 60 years will double from about 11% to 22% [29–31]. Although people are living longer, they are not necessarily healthier than before – nearly a quarter (23%) of the overall global burden of death and illness is in people aged over 60, and much of this burden is attributable to long-term illness caused by diseases such CVD [32–35]. The incidence and prevalence of CVD increase steeply with advancing age [36]. In this context, aging is one of the strongest and most prevalent risk factor for venous thrombosis [37]. Furthermore, venous thrombosis, which leads to pulmonary embolism (PE), is the third most common CVD after myocardial infarction and stroke [38, 39]. The increase of CVD in elderly people is because the aging process is associated with alterations of the structure and function of vascular
components, such as the endothelium, vascular smooth muscle cells (VSMCs) and platelets [40, 41].
3. Nitric oxide pathway and platelet inhibition The primary function of circulating platelets during the hemostatic process is to stop blood loss after tissue trauma [42, 43]. However, the barrier between physiological hemostasis and pathological thrombosis is very narrow, and it has been increasingly recognized that platelets are at least partially liable for the pathological development of atherothrombosis [44–46]. In this context, nitric oxide pathway plays an important role in the inhibition of platelet activation (Fig. 1) [47]. Although NOS is mainly localized to the endothelium, platelets have also been reported to possess a functional L-arginine/NO pathway [48]. Both eNOS and iNOS have been identified in human platelets and megakaryocytic cells [49–51]. In fact, platelet-derived type eNOS and iNOS have been shown to regulate platelet function [52]. The incubation of platelets with NOS substrate L-arginine inhibits platelet aggregation, whereas the NOS inhibitor NG-monomethyl-L-arginine enhances platelet reactivity [53, 54]. Even, platelet agonist-induced NO production is significantly reduced in iNOS-knockout platelets [55]. Meanwhile statins inhibit platelet activation independently on serum cholesterol levels by upregulation of type eNOS [56]. Thus this upregulation of the platelet L-arginine–NO pathway by statins may attenuate the risk of thromboembolic events [57]. The NO in human platelets plays a role in the modulation of platelet function [58, 59]. The antiplatelet effects of NO are mediated through of an increase in levels of both cAMP and cGMP, leading to further signaling events, including phosphorylation of vasodilator-stimulated phosphoprotein (VASP) [60–63]. The actions of cGMP and cAMP are terminated by phosphodiesterases expressed in platelets, which hydrolyzes active cGMP to inactive GMP, and cAMP to AMP [64, 65]. Moreover, other antiplatelet activity of NO is the inhibition of thromboxane receptor in platelet membranes, where activation of kinase G catalyzes phosphorylation of the cytoplasmic carboxyl-terminal domain of the thromboxane receptor [66]. In addition, NO release from platelets
Fig. 1. Platelet inhibition by nitric oxide pathway. AKT = known as protein kinase B; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate; GK = G kinase; GP = glycoprotein; NO = nitric oxide; NOS = nitric oxide synthase; PKA = protein kinase A; PKG = protein kinase G; PPARs = peroxisome proliferator-activated receptors; sGC = soluble guanylate cyclase; TP = thromboxane receptor; VASP = vasodilator-stimulated phosphoprotein; VASP-P = vasodilator-stimulated phosphoprotein phosphorylation.
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markedly inhibits platelet recruitment and thus may limit the progression of arterial thrombosis [67]. ROS have an important role in the control of platelet function. Peroxynitrite (ONOO ) is an oxidant formed from the rapid reaction of superoxide and NO [68, 69]. Peroxynitrite exerts dual effects on platelets, because it presents pro- or anti-antiplatelet activity. Peroxynitriteinduced platelet activation seems to be due to thiol oxidation and an increase in intracellular Ca2+ [70]. The nitration of protein tyrosine residues by peroxynitrite has been associated with pathological conditions [71]. Peroxynitrite rapidly induced tyrosine nitration of proteins in platelet with the same pattern of tyrosine phosphorylation, but with higher intensity, induced by thrombin (platelet activator) [72]. Moreover, peroxynitrite at low concentrations (3–10 microM) inhibited agonist-induced platelet aggregation by a mechanism not dependent on the formation of cGMP [73]. In addition, peroxynitrite may function as a platelet hormone-like COX regulatory mechanism in inflammatory processes [74]. Platelet NO resistance may play an important role in platelet thrombus formation in unstable coronary syndromes [75]. Platelet exhibited hyperaggregability and impaired responsiveness to the antiplatelet effects of NO, possibly by increasing of oxidative stress [76]. Therefore, restoration of antiplatelet activities of NO may potentially have an important therapeutic role [77]. In this context, the treatment with perindopril and ramipril, angiotensin converting enzyme (ACE) inhibitors, significantly improved platelet responses to NO [78, 79]. 4. Antiplatelet activity of natural products via nitric oxide pathway The consumption of a diet rich in functional foods, such as the Mediterranean diet, results in a substantial primary and secondary prevention of CVD [80, 81]. Preliminary studies have demonstrated antiplatelet activity of natural food products and their bioactive components from fruits and vegetables [82–84]. Beta-2 adrenergic and adenosine receptors, and peroxisome proliferator-activated receptors (PPARs) may contribute to modulation of platelet aggregation [85–88]. These receptors allow that human platelets synthesize NO through of NOS activation [89–91]. Dietary components that act as ligands of PPARs include dietary lipids such as n-3 and n-6 fatty acids and their derivatives, polyphenols, alkaloids and terpenoids, among others [92–94]. Magnolol, a natural product from Magnolia officinalis, presents antiplatelet activity by PPARs activation with up-regulation of NO pathway [95–97]. Meanwhile, sesamol, a natural organic compound which is a component of sesame oil, possesses antiplatelet activity with activation of NO pathway [98]. Adenosine, a natural product and endogenous nucleoside, is ligand for the four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3 [99, 100]. In platelet, A2A and A2B receptors leading to stimulation of adenylyl cyclase and consequent elevation of cAMP [87, 88, 101]. Adenosine, which enhances intraplatelet cAMP levels, was determined to also cause an increase in cGMP concentrations through a mechanism that involves NO pathway [102]. Trilinolein is a triacylglycerol with linoleic acid as the only fatty acid residue in all three esterified positions of glycerol. The antiplatelet activity of trilinolein is mediated through an increase in cGMP and that the change in cGMP results from stimulation of NO synthesis [103]. 5. Aging and oxidative stress Oxidative stress has been widely implicated both in aging and in pathogenesis of several neurodegenerative disorders and CVD [104–107]. A large body of evidence indicates that oxidative stress is increased during aging, which is caused by the imbalance between ROS production and antioxidant defense capability (enzymatic and nonenzymatic antioxidants) [108, 109]. A highly significant positive
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correlation between plasma thiol group oxidation and slow decline of antioxidant status in older subjects is predictive of an increased risk of oxidative stress [110]. This is demonstrated by increases of malondialdehyde, 4-hydroxy-2,3-trans-nonenal, glutathione disulfide and by the slight decrease of erythrocytic reduced glutathione and membrane sulphydryl group with age in human [111, 112]. Increased levels of ROS and other reactive oxidants have been reported to cause oxidative modifications of lipids, proteins, and DNA [113]. Thus ROS are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis [114]. Therefore, the increase of ROS generation may contribute to cardiovascular events, including thrombosis [115]. 6. Platelet hyperreactivity and oxidative stress status Aging impairs arterial function through oxidative stress and diminished NO bioavailability [116, 117]. In fact, both ROS and diminished nitric oxide have a direct effect on platelet activation and this may contribute to arterial thrombotic disease in elderly people (Fig. 2). There is abundant evidence that ROS regulate several components of thrombotic processes, including platelet activation [118, 119]. Collageninduced platelet aggregation is associated with a burst of H2O2 that acts as a second messenger by stimulating the arachidonic acid metabolism and phospholipase C pathway [120–122]. NADPH oxidases of the NOX family are important enzymatic sources of ROS [123]. Endothelial cells express four NOX isoforms including the superoxide-generating enzymes NOX1, NOX2, and NOX5 and the hydrogen peroxide-generating enzyme NOX4 [124, 125]. Meanwhile, NOX1 and NOX2 are the isoforms expressed in platelets and important regulators of platelet function in thrombosis [118]. NADPH oxidase and superoxide dismutase are enzymatic sources to generate high levels of H2O2 in platelets from aged mice [126, 127]. NADPH oxidase in platelets seems to play a major role as an intracellular signaling mechanism in the activation of platelets [128]. NADPH oxidase is essentially involved in the redox-sensitive induction of tissue factor (thromboplastin) mRNA expression and surface procoagulant activity by thrombin. This response is mediated by NADPH oxidase-dependent activation of p38 MAP kinase [129]. Therefore, aged mice develop increased susceptibility to both arterial and venous thrombosis and that H2O2-mediated platelet hyperactivation is a likely mechanism leading to this prothrombotic phenotype [130–132]. Furthermore, this may contribute to the increase in circulating monocyte–platelet aggregates observed with age, which may in turn have important pathophysiological consequences [133]. ROS selectively regulate biochemical steps in platelet activation and targeting ROS with site-specific antioxidants may differentially regulate platelet activation [134]. Platelet glutathione peroxidase (GPx) is known to play a pivotal role in controlling the level of lipid hydroperoxides and the inhibition of platelet function by S-nitrosothiols [135]. However, decreased platelet GPx activity observed in platelets from elderly people is associated with platelet activation [136]. Blood platelets are exposed to increasing amounts of ROS during aging. Therefore ROS may regulate platelet function by decreasing NO bioavailability [137]. The impairment of the NO-related signaling pathway may contribute to the platelet dysfunction [138]. In patients with moderate chronic heart failure, there is platelet activation and reduced intraplatelet NO bioavailability due to oxidative stress, which suggests a role for platelets in the prothrombotic state [139]. This functional defect in the platelet NO pathway could contribute to the platelet activation [140, 141]. 7. Clinical significance Thrombotic events such as stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism are common causes of morbidity and mortality in the elderly [142, 143]. Antithrombotic drugs are mainly
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Fig. 2. Role of oxidative stress on platelet hyperreactivity during aging. cGMP = cyclic guanosine monophosphate; GPCR = G protein-coupled receptors; GTP = guanosine triphosphate; NOS = nitric oxide synthase; NO = nitric oxide; PMP = platelet microparticle; ROS = reactive oxygen species; sGC = soluble guanylate cyclase.
of three types: fibrinolytic, anticoagulant and antiplatelet agents. They prevent thrombus extension, recurrence and embolic complications [144]. Antiplatelet agents act by inhibiting thromboxane A2, adenosine diphosphate, thrombin and phosphodiesterase pathways and as it was shown in this article NO pathway. Therefore, platelet inhibitors have been shown to promote dissolution of platelet-rich thrombi [43, 145]. The aging is associated with markedly accelerated atherosclerosis accompanied by an unexpected decrease in aortic antioxidant gene expression [146]. Thus, oxidative stress results in a prothrombotic state and vascular dysfunction that promotes platelet-dependent arterial thrombosis [147–149]. Therefore oxidative stress measurement may help in the early identification of asymptomatic subjects at risk of thrombosis [150, 151]. In addition, ROS inhibitors and platelet-derived NO may represent a novel anti-platelet approach [152, 153]. 8. Conclusion There is abundant evidence that oxidative stress in aging regulates several components of thrombotic processes, including platelet activation. Thus oxidative stress induced platelet hyperreactivity by decreasing NO bioavailability. Therefore oxidative stress may represent a novel anti-platelet approach and help in the early identification of asymptomatic subjects at risk of thrombosis. Conflict of interest The authors have no conflicts of interest to disclose. Acknowledgements This work was funded by the CONICYT REGIONAL/GORE MAULE/ CEAP/R09I2001, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), and supported by grant no. 1130216 (I.P., M.G., R.M., M.A., J.C.) from Fondecyt, Chile. Also Eduardo Fuentes thanks FONDECYT (FONDECYT Initiation No. 11140142).
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Review article
Role of oxidative stress on platelet hyperreactivity during aging Eduardo Fuentes ⁎, Iván Palomo ⁎ a Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca, Chile b Centro de Estudios en Alimentos Procesados (CEAP), CONICYT-Regional, Gore Maule R09I2001, Chile
a r t i c l e
i n f o
Article history: Received 17 October 2015 Received in revised form 3 February 2016 Accepted 8 February 2016 Available online 9 February 2016 Keywords: Aging Oxidative stress Nitric oxide Platelet activation Thrombosis
a b s t r a c t Thrombotic events are common causes of morbidity and mortality in the elderly. Age-accelerated vascular injury is commonly considered to result from increased oxidative stress. There is abundant evidence that oxidative stress regulate several components of thrombotic processes, including platelet activation. Thus oxidative stress can trigger platelet hyperreactivity by decreasing nitric oxide bioavailability. Therefore oxidative stress measurement may help in the early identification of asymptomatic subjects at risk of thrombosis. In addition, oxidative stress inhibitors and platelet-derived nitric oxide may represent a novel anti-aggregation/-activation approach. In this article the relative contribution of oxidative stress and platelet activation in aging is explored. © 2016 Elsevier Inc. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 2. Aging and cardiovascular diseases . . . . . . . . . . . . . . 3. Nitric oxide pathway and platelet inhibition . . . . . . . . . . 4. Antiplatelet activity of natural products via nitric oxide pathway 5. Aging and oxidative stress . . . . . . . . . . . . . . . . . . 6. Platelet hyperreactivity and oxidative stress status . . . . . . . 7. Clinical significance . . . . . . . . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Cardiovascular diseases (CVD) increase in incidence in the elderly, a tendency dependent on the age-related changes in vascular and hemostatic systems [1]. Age-accelerated vascular injury is commonly considered to result from increased oxidative stress [2]. In these conditions, aging is associated with immunosenescence and accompanied by a chronic inflammatory state which contributes to metabolic syndrome, diabetes and their cardiovascular consequences [3–5]. Age is a ⁎ Corresponding authors at: Immunology and Haematology Laboratory, Faculty of Health Sciences, Universidad de Talca, Casilla: 747, Talca, Chile. E-mail addresses: [email protected] (E. Fuentes), [email protected] (I. Palomo).
http://dx.doi.org/10.1016/j.lfs.2016.02.026 0024-3205/© 2016 Elsevier Inc. All rights reserved.
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nonmodifiable risk factor for atherosclerosis. Older animals develop more extensive atherosclerosis than younger animals when both groups are fed an atherogenic diet [6, 7]. Platelets have a dynamic functional repertoire that mediates haemostatic function [8]. However, platelet function is altered in older adults [9–11]. Therefore in aging, the correlation between platelet aggregation in whole blood and platelet-arterial wall interactions (in vitro and in vivo) may contribute to CVD [12]. Nitric oxide (NO) in human is produced from L-arginine by three enzymes called nitric oxide synthases (NOS): inducible (iNOS), neuronal (nNOS) and endothelial (eNOS), which differ in their dependence on Ca2+, as well as in their expression and activities. The eNOS and iNOS have been crucial in cardiovascular protection [13, 14].
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The NO is present in platelets and regulates their platelet function [15, 16]. NO stimulates cyclic guanosine monophosphate (cGMP) synthesis by activating soluble guanylyl cyclase (sGC), which plays a crucial role in preventing platelet activation [17, 18]. However, metabolic abnormalities as a result of aging cause platelet hyperaggregability involving enhanced intraplatelet reactive oxygen species (ROS) production and decreased NO bioavailability [19, 20]. NO is a reactive free radical that can participate in several types of redox reactions, some that mediated its biological effects and others that limit its activity. Inactivation of NO occurs largely through oxidative reactions mediated by ROS [21, 22]. Increased generation of ROS is found in a variety of vascular disorders and during aging [23–26]. The nitric oxide pathway plays an important role in the inhibition of platelet activation and thrombus formation. Yet, the role of oxidative stress on platelet function and thrombus risk during aging yet to be fully elucidated. In this article the relative contribution of oxidative stress and platelet hyperreactivity during aging is explored.
2. Aging and cardiovascular diseases Most studies of older populations in developed countries show a decrease in the prevalence of disabilities, and an increase in chronic diseases over the past decades [27, 28]. The world population is rapidly aging. Between 2000 and 2050, the proportion of the world's population over 60 years will double from about 11% to 22% [29–31]. Although people are living longer, they are not necessarily healthier than before – nearly a quarter (23%) of the overall global burden of death and illness is in people aged over 60, and much of this burden is attributable to long-term illness caused by diseases such CVD [32–35]. The incidence and prevalence of CVD increase steeply with advancing age [36]. In this context, aging is one of the strongest and most prevalent risk factor for venous thrombosis [37]. Furthermore, venous thrombosis, which leads to pulmonary embolism (PE), is the third most common CVD after myocardial infarction and stroke [38, 39]. The increase of CVD in elderly people is because the aging process is associated with alterations of the structure and function of vascular
components, such as the endothelium, vascular smooth muscle cells (VSMCs) and platelets [40, 41].
3. Nitric oxide pathway and platelet inhibition The primary function of circulating platelets during the hemostatic process is to stop blood loss after tissue trauma [42, 43]. However, the barrier between physiological hemostasis and pathological thrombosis is very narrow, and it has been increasingly recognized that platelets are at least partially liable for the pathological development of atherothrombosis [44–46]. In this context, nitric oxide pathway plays an important role in the inhibition of platelet activation (Fig. 1) [47]. Although NOS is mainly localized to the endothelium, platelets have also been reported to possess a functional L-arginine/NO pathway [48]. Both eNOS and iNOS have been identified in human platelets and megakaryocytic cells [49–51]. In fact, platelet-derived type eNOS and iNOS have been shown to regulate platelet function [52]. The incubation of platelets with NOS substrate L-arginine inhibits platelet aggregation, whereas the NOS inhibitor NG-monomethyl-L-arginine enhances platelet reactivity [53, 54]. Even, platelet agonist-induced NO production is significantly reduced in iNOS-knockout platelets [55]. Meanwhile statins inhibit platelet activation independently on serum cholesterol levels by upregulation of type eNOS [56]. Thus this upregulation of the platelet L-arginine–NO pathway by statins may attenuate the risk of thromboembolic events [57]. The NO in human platelets plays a role in the modulation of platelet function [58, 59]. The antiplatelet effects of NO are mediated through of an increase in levels of both cAMP and cGMP, leading to further signaling events, including phosphorylation of vasodilator-stimulated phosphoprotein (VASP) [60–63]. The actions of cGMP and cAMP are terminated by phosphodiesterases expressed in platelets, which hydrolyzes active cGMP to inactive GMP, and cAMP to AMP [64, 65]. Moreover, other antiplatelet activity of NO is the inhibition of thromboxane receptor in platelet membranes, where activation of kinase G catalyzes phosphorylation of the cytoplasmic carboxyl-terminal domain of the thromboxane receptor [66]. In addition, NO release from platelets
Fig. 1. Platelet inhibition by nitric oxide pathway. AKT = known as protein kinase B; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate; GK = G kinase; GP = glycoprotein; NO = nitric oxide; NOS = nitric oxide synthase; PKA = protein kinase A; PKG = protein kinase G; PPARs = peroxisome proliferator-activated receptors; sGC = soluble guanylate cyclase; TP = thromboxane receptor; VASP = vasodilator-stimulated phosphoprotein; VASP-P = vasodilator-stimulated phosphoprotein phosphorylation.
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markedly inhibits platelet recruitment and thus may limit the progression of arterial thrombosis [67]. ROS have an important role in the control of platelet function. Peroxynitrite (ONOO ) is an oxidant formed from the rapid reaction of superoxide and NO [68, 69]. Peroxynitrite exerts dual effects on platelets, because it presents pro- or anti-antiplatelet activity. Peroxynitriteinduced platelet activation seems to be due to thiol oxidation and an increase in intracellular Ca2+ [70]. The nitration of protein tyrosine residues by peroxynitrite has been associated with pathological conditions [71]. Peroxynitrite rapidly induced tyrosine nitration of proteins in platelet with the same pattern of tyrosine phosphorylation, but with higher intensity, induced by thrombin (platelet activator) [72]. Moreover, peroxynitrite at low concentrations (3–10 microM) inhibited agonist-induced platelet aggregation by a mechanism not dependent on the formation of cGMP [73]. In addition, peroxynitrite may function as a platelet hormone-like COX regulatory mechanism in inflammatory processes [74]. Platelet NO resistance may play an important role in platelet thrombus formation in unstable coronary syndromes [75]. Platelet exhibited hyperaggregability and impaired responsiveness to the antiplatelet effects of NO, possibly by increasing of oxidative stress [76]. Therefore, restoration of antiplatelet activities of NO may potentially have an important therapeutic role [77]. In this context, the treatment with perindopril and ramipril, angiotensin converting enzyme (ACE) inhibitors, significantly improved platelet responses to NO [78, 79]. 4. Antiplatelet activity of natural products via nitric oxide pathway The consumption of a diet rich in functional foods, such as the Mediterranean diet, results in a substantial primary and secondary prevention of CVD [80, 81]. Preliminary studies have demonstrated antiplatelet activity of natural food products and their bioactive components from fruits and vegetables [82–84]. Beta-2 adrenergic and adenosine receptors, and peroxisome proliferator-activated receptors (PPARs) may contribute to modulation of platelet aggregation [85–88]. These receptors allow that human platelets synthesize NO through of NOS activation [89–91]. Dietary components that act as ligands of PPARs include dietary lipids such as n-3 and n-6 fatty acids and their derivatives, polyphenols, alkaloids and terpenoids, among others [92–94]. Magnolol, a natural product from Magnolia officinalis, presents antiplatelet activity by PPARs activation with up-regulation of NO pathway [95–97]. Meanwhile, sesamol, a natural organic compound which is a component of sesame oil, possesses antiplatelet activity with activation of NO pathway [98]. Adenosine, a natural product and endogenous nucleoside, is ligand for the four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3 [99, 100]. In platelet, A2A and A2B receptors leading to stimulation of adenylyl cyclase and consequent elevation of cAMP [87, 88, 101]. Adenosine, which enhances intraplatelet cAMP levels, was determined to also cause an increase in cGMP concentrations through a mechanism that involves NO pathway [102]. Trilinolein is a triacylglycerol with linoleic acid as the only fatty acid residue in all three esterified positions of glycerol. The antiplatelet activity of trilinolein is mediated through an increase in cGMP and that the change in cGMP results from stimulation of NO synthesis [103]. 5. Aging and oxidative stress Oxidative stress has been widely implicated both in aging and in pathogenesis of several neurodegenerative disorders and CVD [104–107]. A large body of evidence indicates that oxidative stress is increased during aging, which is caused by the imbalance between ROS production and antioxidant defense capability (enzymatic and nonenzymatic antioxidants) [108, 109]. A highly significant positive
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correlation between plasma thiol group oxidation and slow decline of antioxidant status in older subjects is predictive of an increased risk of oxidative stress [110]. This is demonstrated by increases of malondialdehyde, 4-hydroxy-2,3-trans-nonenal, glutathione disulfide and by the slight decrease of erythrocytic reduced glutathione and membrane sulphydryl group with age in human [111, 112]. Increased levels of ROS and other reactive oxidants have been reported to cause oxidative modifications of lipids, proteins, and DNA [113]. Thus ROS are key mediators of signaling pathways that underlie vascular inflammation in atherogenesis [114]. Therefore, the increase of ROS generation may contribute to cardiovascular events, including thrombosis [115]. 6. Platelet hyperreactivity and oxidative stress status Aging impairs arterial function through oxidative stress and diminished NO bioavailability [116, 117]. In fact, both ROS and diminished nitric oxide have a direct effect on platelet activation and this may contribute to arterial thrombotic disease in elderly people (Fig. 2). There is abundant evidence that ROS regulate several components of thrombotic processes, including platelet activation [118, 119]. Collageninduced platelet aggregation is associated with a burst of H2O2 that acts as a second messenger by stimulating the arachidonic acid metabolism and phospholipase C pathway [120–122]. NADPH oxidases of the NOX family are important enzymatic sources of ROS [123]. Endothelial cells express four NOX isoforms including the superoxide-generating enzymes NOX1, NOX2, and NOX5 and the hydrogen peroxide-generating enzyme NOX4 [124, 125]. Meanwhile, NOX1 and NOX2 are the isoforms expressed in platelets and important regulators of platelet function in thrombosis [118]. NADPH oxidase and superoxide dismutase are enzymatic sources to generate high levels of H2O2 in platelets from aged mice [126, 127]. NADPH oxidase in platelets seems to play a major role as an intracellular signaling mechanism in the activation of platelets [128]. NADPH oxidase is essentially involved in the redox-sensitive induction of tissue factor (thromboplastin) mRNA expression and surface procoagulant activity by thrombin. This response is mediated by NADPH oxidase-dependent activation of p38 MAP kinase [129]. Therefore, aged mice develop increased susceptibility to both arterial and venous thrombosis and that H2O2-mediated platelet hyperactivation is a likely mechanism leading to this prothrombotic phenotype [130–132]. Furthermore, this may contribute to the increase in circulating monocyte–platelet aggregates observed with age, which may in turn have important pathophysiological consequences [133]. ROS selectively regulate biochemical steps in platelet activation and targeting ROS with site-specific antioxidants may differentially regulate platelet activation [134]. Platelet glutathione peroxidase (GPx) is known to play a pivotal role in controlling the level of lipid hydroperoxides and the inhibition of platelet function by S-nitrosothiols [135]. However, decreased platelet GPx activity observed in platelets from elderly people is associated with platelet activation [136]. Blood platelets are exposed to increasing amounts of ROS during aging. Therefore ROS may regulate platelet function by decreasing NO bioavailability [137]. The impairment of the NO-related signaling pathway may contribute to the platelet dysfunction [138]. In patients with moderate chronic heart failure, there is platelet activation and reduced intraplatelet NO bioavailability due to oxidative stress, which suggests a role for platelets in the prothrombotic state [139]. This functional defect in the platelet NO pathway could contribute to the platelet activation [140, 141]. 7. Clinical significance Thrombotic events such as stroke, myocardial infarction, deep vein thrombosis, and pulmonary embolism are common causes of morbidity and mortality in the elderly [142, 143]. Antithrombotic drugs are mainly
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Fig. 2. Role of oxidative stress on platelet hyperreactivity during aging. cGMP = cyclic guanosine monophosphate; GPCR = G protein-coupled receptors; GTP = guanosine triphosphate; NOS = nitric oxide synthase; NO = nitric oxide; PMP = platelet microparticle; ROS = reactive oxygen species; sGC = soluble guanylate cyclase.
of three types: fibrinolytic, anticoagulant and antiplatelet agents. They prevent thrombus extension, recurrence and embolic complications [144]. Antiplatelet agents act by inhibiting thromboxane A2, adenosine diphosphate, thrombin and phosphodiesterase pathways and as it was shown in this article NO pathway. Therefore, platelet inhibitors have been shown to promote dissolution of platelet-rich thrombi [43, 145]. The aging is associated with markedly accelerated atherosclerosis accompanied by an unexpected decrease in aortic antioxidant gene expression [146]. Thus, oxidative stress results in a prothrombotic state and vascular dysfunction that promotes platelet-dependent arterial thrombosis [147–149]. Therefore oxidative stress measurement may help in the early identification of asymptomatic subjects at risk of thrombosis [150, 151]. In addition, ROS inhibitors and platelet-derived NO may represent a novel anti-platelet approach [152, 153]. 8. Conclusion There is abundant evidence that oxidative stress in aging regulates several components of thrombotic processes, including platelet activation. Thus oxidative stress induced platelet hyperreactivity by decreasing NO bioavailability. Therefore oxidative stress may represent a novel anti-platelet approach and help in the early identification of asymptomatic subjects at risk of thrombosis. Conflict of interest The authors have no conflicts of interest to disclose. Acknowledgements This work was funded by the CONICYT REGIONAL/GORE MAULE/ CEAP/R09I2001, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), and supported by grant no. 1130216 (I.P., M.G., R.M., M.A., J.C.) from Fondecyt, Chile. Also Eduardo Fuentes thanks FONDECYT (FONDECYT Initiation No. 11140142).
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