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Reactive Oxygen Species in Venous Thrombosis

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Reactive Oxygen Species in Venous Thrombosis International Journal of Molecular Sciences Review Reactive Oxygen Species in Venous Thrombosis 1 2 3 3, 3, , Clemens Gutmann , Richard Siow , Adam M. Gwozdz , Prakash Saha y and Alberto Smith y * 1 King’s British Heart Foundation Centre, King’s College London, 125 Coldharbour Lane, London SE5 9NU, UK; [email protected] 2 Vascular Biology & Inflammation Section, School of Cardiovascular Medicine & Sciences, British Heart Foundation of Research Excellence, King’s College London, SE1 9NH, UK; [email protected] 3 Academic Department of Surgery, School of Cardiovascular Medicine & Sciences, British Heart Foundation of Research Excellence, King’s College London, London SE1 7EH, UK; [email protected] (A.M.G.); [email protected] (P.S.) * Correspondence: [email protected]; Tel.: +44-207-188-0216 These two authors contribute equally to this work. y Received: 14 February 2020; Accepted: 4 March 2020; Published: 11 March 2020 Abstract: Reactive oxygen species (ROS) have physiological roles as second messengers, but can also exert detrimental modifications on DNA, proteins and lipids if resulting from enhanced generation or reduced antioxidant defense (oxidative stress). Venous thrombus (DVT) formation and resolution are influenced by ROS through modulation of the coagulation, fibrinolysis, proteolysis and the complement system, as well as the regulation of effector cells such as platelets, endothelial cells, erythrocytes, neutrophils, mast cells, monocytes and fibroblasts. Many conditions that carry an elevated risk of venous thrombosis, such as the Antiphospholipid Syndrome, have alterations in their redox homeostasis. Dietary and pharmacological antioxidants can modulate several important processes involved in DVT formation, but their overall effect is unknown and there are no recommendations regarding their use. The development of novel antioxidant treatments that aim to abrogate the formation of DVT or promote its resolution will depend on the identification of targets that enable ROS modulation confined to their site of interest in order to prevent off-target effects on physiological redox mechanisms. Subgroups of patients with increased systemic oxidative stress might benefit from unspecific antioxidant treatment, but more clinical studies are needed to bring clarity to this issue. Keywords: DVT; venous thrombosis; reactive oxygen species; oxidative stress; redox regulation; anticoagulation; thrombus resolution; dietary antioxidants; antioxidant defenses 1. Introduction Deep vein thrombosis (DVT) accounts for around 10 million cases of thrombosis per year and is the third most prevalent cardiovascular disease (CVD) after myocardial infarction and stroke. The incidence of DVT increases with age and its complications are ranked among the top causes of death and poor quality of life in western countries [1]. As a complication of DVT, pulmonary embolism is the main driver of DVT-associated mortality. Venous reflux in DVT-damaged veins (post-thrombotic syndrome) is, however, the main driver of DVT-associated morbidity, causing pain, swelling and, when severe, chronic skin ulceration. DVT is therefore a major contributor to the global disease burden [1]. Anticoagulation is the most common approach taken when treating DVT, but although these drugs inhibit thrombus propagation, they are associated with an increased risk of pathological bleeding such as stroke. Anticoagulants also have little effect on resolving existing thrombi, which occurs over time through a natural process of organization. Although enhanced natural thrombus resolution Int. J. Mol. Sci. 2020, 21, 1918; doi:10.3390/ijms21061918 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 1918 2 of 27 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 27 is associated with improved long-term outcome [2], interventional (endovascular or open surgery) approachesresolution of is thrombusassociated resolutionwith improved are notlong-term always outcome effective [2], and interventional are associated (endovascular with side eorff ectsopen that limitsurgery) their use approaches in the majority of thrombus of patients resolution [3]. The are developmentnot always effective of novel and treatment are associated modalities, with side which blockeffects thrombus that limit formation their use and in/or the enhance majority thrombus of patients resolution [3]. The but, development at the same of time, novel carry treatment fewer side effects,modalities, are therefore which desirableblock thrombus and will formation only come and/or from enhance an improved thrombus understanding resolution but, of at the the regulatory same mechanismstime, carry involved fewer side in these effects, processes. are therefore desirable and will only come from an improved understandingAs discussed of in the this regulatory review, numerousmechanisms studies involved have in these shown processes. that both thrombus formation and its resolutionAs discussed may be in regulated this review, by numerous reactive oxygen studies species have shown (ROS). that Certain both thrombus intracellular formation ROS, suchand as its resolution may be regulated by reactive oxygen species (ROS). Certain intracellular ROS, such as superoxide (O2−) and hydrogen peroxide (H2O2), have physiological functions as second messengers superoxide (O2-) and hydrogen peroxide (H2O2), have physiological functions as second messengers in signalling pathways, while pathologic generation or decreased antioxidant scavenging of extra- in signalling pathways, while pathologic generation or decreased antioxidant scavenging of extra- and intracellular ROS (oxidative stress) lead to damage of proteins, lipids and DNA, resulting in and intracellular ROS (oxidative stress) lead to damage of proteins, lipids and DNA, resulting in modified functions of these molecules as well as dose-dependent programmed or unprogrammed cell modified functions of these molecules as well as dose-dependent programmed or unprogrammed deathcell [death4]. ROS [4]. are ROS generated are generated as by-products as by-products of aerobic of aerobic respiration respiration within within mitochondria mitochondria [5], during[5], oxidativeduring foldingoxidative of folding proteins of (endoplasmicproteins (endoplasmic reticulum reticulum [6]), as well [6]), asas enzymes well as ofenzymes the cytochrome of the p450cytochrome (endoplasmic p450 reticulum (endoplasmic and mitochondriareticulum and [7 ]),mitochondria cyclooxygenase [7]), (endoplasmiccyclooxygenase reticulum, (endoplasmic nuclear envelopereticulum, [8]), nuclear lipoxygenase envelope (nuclear [8]), lipoxygenase envelope, cytoplasm (nuclear envelope, [9]) and NADPHcytoplasm oxidase [9]) and (NOX) NADPH family (endoplasmicoxidase (NOX) reticulum, family (endoplasmic endosomal and reticulum, plasma membranesendosomal and [10 ],plasma Figure membranes1)[ 4]. NOX [10], enzymes Figure appear 1) [4]. to be theNOX most enzymes important appear source to be the for ROSmost involvedimportant in source processes for ROS related involved to DVT. in processes Depending related on isotype to DVT. and - cellDepending type, these on membrane-bound isotype and cell enzymestype, these release membrane-bound O2− into intra- enzymes or extracellular release O compartments2 into intra- or [10 ]. Superoxideextracellular may compartments then react (spontaneously [10]. Superoxide or catalysed may then by react superoxide (spontaneously dismutase) or tocatalysed form H 2Oby2 . If 2 2 2 2 2+ 2+ H2Osuperoxide2 molecules dismutase) encounter to form transition H O . If metals H O molecules such as Feencounterions, transition they can metals be converted such as Fe into ions, highly reactivethey can hydroxyl be converted radicals into ( highlyOH, Fentonreactive Reactionhydroxyl [radicals11]), leading (•OH, toFenton oxidative Reaction damage [11]), leading [4]. Several to • antioxidantoxidative enzymesdamage [4]. (superoxide Several antioxidant dismutase [enzymes12], catalase (superoxide [13], glutathione dismutase peroxidases [12], catalase [14 ],[13], heme oxygenaseglutathione [15 ],peroxidases thioredoxin [14], system heme [16 oxygenase]) and small [15], molecule thioredoxin antioxidants system (glutathione[16]) and small [17 ],molecule vitamin A, antioxidants (glutathione [17], vitamin A, C and E [18]) are produced to scavenge ROS, thereby C and E [18]) are produced to scavenge ROS, thereby limiting these detrimental effects [18]. These limiting these detrimental effects [18]. These redox mechanisms are essential for normal physiological redox mechanisms are essential for normal physiological homeostasis, but their dysregulation may homeostasis, but their dysregulation may have pathological consequences. In this review, we provide have pathological consequences. In this review, we provide an overview of how ROS and perturbations an overview of how ROS and perturbations in redox homeostasis may be involved in the mechanisms in redoxthat give homeostasis rise to the mayformation be involved and resolution in the mechanisms of venous thrombi. that give We rise also to aim the to formation highlight and the resolutionclinical of venouspotential thrombi. of targeting We these also aim processes. to highlight the clinical potential of targeting these processes. FigureFigure 1. Major1. Major sources sources of reactive of reactive oxygen oxygen species species (ROS) (ROS) and antioxidant and antioxidant defense defense mechanisms. mechanisms. NADPH oxidasesNADPH (NOX; oxidases highlighted (NOX; highlighted in red) appear in red)
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