Platelet NAD(P)H-oxidase–generated ROS production regulates αIIbβ3-integrin activation independent of the NO/cGMP pathway

Begonja, Antonija Jurak; Gambaryan, Stepan; Geiger, Jörg; Aktas, Barsom; Požgajová, Miroslava; Nieswandt, Bernhard; Walter, Ulrich

doi:10.1182/blood-2005-03-1047

Cited by 204 publications

(177 citation statements)

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“…In control experiments, we found that NOX2 deletion or catalase treatment reduced intracellular ROS generation in both resting and activated mouse platelets and that compared with NOX2 deletion, treatment of NOX2 KO platelets with catalase further decreased ROS production (supplemental Figure 3A), implying that other pathways may also generate ROS. Consistent with previous studies, 13 extracellular ROS were not detected in activated platelets (data not shown). These results suggest that platelet NOX2-generated ROS such as H 2 O 2 regulate P-selectin exposure induced by submaximal concentrations of thrombin.…”

Section: Platelet Nox2 Regulates P-selectin Exposure Upon Agonist Stisupporting

confidence: 93%

“…12 However, NOX5 is expressed only in the vasculature of humans. Compared with platelets that produce low amounts of ROS through NOX1 and NOX2, 13,14 neutrophils rapidly generate much larger amounts of ROS via NOX2 after cell activation. 15 The NOX2 enzyme consists of membrane subunits (p22 phox and gp91 phox ) and cytosolic components (p47 phox , p67 phox , p40 phox , and small GTPase Rac1/2), and generates O 2 ·-by transferring 1 electron from NADPH to molecular oxygen.…”

Section: Introductionmentioning

confidence: 99%

“…11 Previous studies showed that glycoprotein VI (GPVI)-mediated platelet aggregation and ROS generation are significantly impaired by pretreatment with nonselective NOX inhibitors and ROS scavengers. 13,16 Platelets from patients deficient in gp91 phox (X-linked chronic granulomatous disease [X-CGD]) showed defects in CD40 ligand expression induced by various agonists and production of ROS. 17 Furthermore, clinical studies with X-CGD patients demonstrated that NOX2 deficiency increases serum levels of nitrite and nitrate as markers of nitric oxide generation, thereby enhancing arterial dilation.…”

Section: Introductionmentioning

confidence: 99%

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NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation

Kim¹,

Li²,

Tseng

et al. 2015

Blood

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Key Points• NOX2-generated ROS regulate the function of surface receptors required for platelet-neutrophil interactions during vascular inflammation.Platelet-leukocyte interactions on activated endothelial cells play an important role during microvascular occlusion under oxidative stress conditions. However, it remains poorly understood how neutrophil-platelet interactions are regulated during vascular inflammation. By using intravital microscopy with mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their bone marrow chimera, we demonstrated that NOX2 from both hematopoietic and endothelial cells is crucial for neutrophil-platelet interactions during tumor necrosis factor alpha-induced venular inflammation. Platelet NOX2-produced reactive oxygen species (ROS) regulated P-selectin exposure upon agonist stimulation and the ligand-binding function of glycoprotein Iba. Furthermore, neutrophil NOX2-generated ROS enhanced the activation and ligand-binding activity of aMb2 integrin following N-formyl-methionyl-leucyl phenylalanine stimulation. Studies with isolated cells and a mouse model of hepatic ischemia/reperfusion injury revealed that NOX2 from both platelets and neutrophils is required for cell-cell interactions, which contribute to the pathology of hepatic ischemia/reperfusion injury. Platelet NOX2 modulated intracellular Ca 21 release but not store-operated Ca 21 entry (SOCE), whereas neutrophil NOX2 was crucial for SOCE but not intracellular Ca 21 release. Different regulation of Ca 21 signaling by platelet and neutrophil NOX2 correlated with differences in the phosphorylation of AKT, ERK, and p38MAPK. Our results indicate that platelet and neutrophil NOX2-produced ROS are critical for the function of surface receptors essential for neutrophil-platelet interactions during vascular inflammation. (Blood. 2015;126(16):1952-1964

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Section: Platelet Nox2 Regulates P-selectin Exposure Upon Agonist Stisupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation

Kim¹,

Li²,

Tseng

et al. 2015

Blood

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“…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 gp91 phox -deficient patients produce only a small amount of reactive oxygen species.…”

Section: Reactive Oxygen Species and Platelet Functionmentioning

confidence: 99%

Oxidative Stress and Platelets

Freedman

2008

ATVB

290

167

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Abstract-Platelet-dependent thrombus formation may be influenced by alteration of platelet or vascular redox state, the presence of endogenous or exogenous antioxidants, as well as the formation of reactive oxygen and nitrogen species. Specifically, settings and pathways that influence the formation of superoxide and nitric oxide, as well as their metabolism, may influence platelet function and thrombus formation. Although some antioxidant regimens have been associated with bleeding and hemorrhagic stroke, the therapeutic value of antioxidants in clinical syndromes that lead to platelet-dependent thrombosis is not clear, as supplemental antioxidants have not been generally associated with better cardiovascular outcome. R edox 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 AntioxidantsThrombus formation within a coronary vessel is the precipitating event in myocardial infarction and unstable angina. 4 Normally, the intact endothelium prevents adhesion and activation of platelets. Adhesion of platelets to the endothelium is prevented by several mechanisms, including endothelial cell production of prostacyclin and nitric oxide (NO). 5,6 The occurrence of superficial intimal injury caused by endothelial denudation and deep intimal injury caused by plaque rupture expose collagen and von Willebrand factor (vWF) to platelets. Platelets then adhere directly to collagen or indirectly via the binding of vWF to the glycoprotein (GP) Ib/IX matrix. Local platelet activation stimulates further thrombus formation and additional platelet recruitment by supporting ce...

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“…In contrast, there are several studies demonstrating that CS actually reduces the oxidantproducing capacity of neutrophils while elevating adhesion molecule expression (17,18), although less is known about monocytes and lymphocytes. With the recent abundance in the literature on the interactions between the inflammatory and thrombogenic pathways induced in many disease states, it would be interesting to determine whether platelets, which are activated by CS (4,6) and can themselves produce superoxide from NAD(P)H oxidase (3,7,13), participate in the vascular oxidative stress and inflammation generated during smoking.…”

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confidence: 99%

NAD(P)H oxidase: where there's smoke, there's fire

Stokes¹

2007

American Journal of Physiology-Heart and Circulatory Physiology

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Platelet NAD(P)H-oxidase–generated ROS production regulates αIIbβ3-integrin activation independent of the NO/cGMP pathway

Cited by 204 publications

References 23 publications

NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation

NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation

Oxidative Stress and Platelets

NAD(P)H oxidase: where there's smoke, there's fire

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