Superoxide Dismutase 2 is dispensable for platelet function

Fidler, Trevor P.; Rowley, Jesse W.; Araujo, Claudia V. de; Boudreau, Luc H.; Marti, Alex; Souvenir, Rhonda; Dale, Kali; Boilard, Éric; Weyrich, Andrew S.

doi:10.1160/th17-03-0174

Cited by 21 publications

(18 citation statements)

References 33 publications

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“…Overall, our findings are consistent with prior studies demonstrating a role for ROS in platelet function 5,8,43,44 and further suggest that multiple oxidative pathways are involved in regulating platelet aggregation and thrombi formation. These observations are also in concordance with recent reports implicating mitochondrial ROS in platelet activation in certain disease states.…”

Section: Discussionsupporting

confidence: 92%

Nox2 NADPH oxidase is dispensable for platelet activation or arterial thrombosis in mice

Sonkar¹,

Kumar²,

Jensen³

et al. 2019

Blood Advances

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Deficiency of the Nox2 (gp91phox) catalytic subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a genetic cause of X-linked chronic granulomatous disease, a condition in which patients are prone to infection resulting from the loss of oxidant production by neutrophils. Some studies have suggested a role for superoxide derived from Nox2 NADPH oxidase in platelet activation and thrombosis, but data are conflicting. Using a rigorous and comprehensive approach, we tested the hypothesis that genetic deficiency of Nox2 attenuates platelet activation and arterial thrombosis. Our study was designed to test the genotype differences within male and female mice. Using chloromethyl-dichlorodihydrofluorescein diacetate, a fluorescent dye, as well as high-performance liquid chromatography analysis with dihydroethidium as a probe to detect intracellular reactive oxygen species (ROS), we observed no genotype differences in ROS levels in platelets. Similarly, there were no genotype-dependent differences in levels of mitochondrial ROS. In addition, we did not observe any genotype-associated differences in platelet activation, adhesion, secretion, or aggregation in male or female mice. Platelets from chronic granulomatous disease patients exhibited similar adhesion and aggregation responses as platelets from healthy subjects. Susceptibility to carotid artery thrombosis in a photochemical injury model was similar in wild-type and Nox2-deficient male or female mice. Our findings indicate that Nox2 NADPH oxidase is not an essential source of platelet ROS or a mediator of platelet activation or arterial thrombosis in large vessels, such as the carotid artery.

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Section: Discussionsupporting

confidence: 92%

Nox2 NADPH oxidase is dispensable for platelet activation or arterial thrombosis in mice

Sonkar¹,

Kumar²,

Jensen³

et al. 2019

Blood Advances

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“…Recently, Fidler and coworkers demonstrated that SOD2-KO platelets showed increased mitochondrial ROS; however, total platelet ROS content remained unchanged. Furthermore, deletion of SOD2 did not alter tail-bleeding or arterial thrombosis in vivo, suggesting that SOD2 is dispensable for platelet redox balance [ 81 , 82 ].…”

Section: Endogenous and Exogenous Antioxidant Systems As Regulatormentioning

confidence: 99%

ROS in Platelet Biology: Functional Aspects and Methodological Insights

Masselli

Pozzi

Vaccarezza

et al. 2020

IJMS

127

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Reactive oxygen species (ROS) and mitochondria play a pivotal role in regulating platelet functions. Platelet activation determines a drastic change in redox balance and in platelet metabolism. Indeed, several signaling pathways have been demonstrated to induce ROS production by NAPDH oxidase (NOX) and mitochondria, upon platelet activation. Platelet-derived ROS, in turn, boost further ROS production and consequent platelet activation, adhesion and recruitment in an auto-amplifying loop. This vicious circle results in a platelet procoagulant phenotype and apoptosis, both accounting for the high thrombotic risk in oxidative stress-related diseases. This review sought to elucidate molecular mechanisms underlying ROS production upon platelet activation and the effects of an altered redox balance on platelet function, focusing on the main advances that have been made in platelet redox biology. Furthermore, given the increasing interest in this field, we also describe the up-to-date methods for detecting platelets, ROS and the platelet bioenergetic profile, which have been proposed as potential disease biomarkers.

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“…Blood was isolated into 1:20 acid citrate dextrose through carotid artery cannulation as previously described (8). For GLUT1 protein analysis and Seahorse analysis, platelets were negatively depleted of leukocytes and red blood cells by incubation with CD45 and Terr119 microbeads (Milteny Biotec, Cambridge, MA).…”

Section: Platelet Isolationsmentioning

confidence: 99%

Glucose Metabolism Is Required for Platelet Hyperactivation in a Murine Model of Type 1 Diabetes

et al. 2019

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Patients with type 1 diabetes mellitus (T1DM) have increased thrombosis and platelet activation. The mechanisms for platelet hyperactivation in diabetes are incompletely understood. T1DM is accompanied by hyperglycemia, dyslipidemia, and increased inflammation in addition to an altered hormonal milieu. In vitro analysis of platelets revealed that normal glucose reduces platelet activation whereas hyperglycemic conditions increase platelet activation. We therefore hypothesized that hyperglycemia increases platelet glucose utilization, which increases platelet activation to promote thrombosis. Glucose uptake and glycolysis were increased in platelets isolated from mice given streptozotocin (STZ) to induce T1DM in concert with induction of GLUT3. Platelets from STZ-induced diabetic mice exhibited increased activation after administration of proteaseactivated receptor 4 peptide and convulxin. In contrast, platelets isolated from GLUT1 and GLUT3 double-knockout (DKO) mice, which lack the ability to use glucose, failed to increase activation in hyperglycemic mice. Diabetic mice displayed decreased survival in a collagen/epinephrine-induced pulmonary embolism model of in vivo platelet activation relative to nondiabetic controls. Survival after pulmonary embolism was increased in diabetic DKO mice relative to nondiabetic controls. These data reveal that increased platelet glucose metabolism in vivo contributes to increased platelet activation and thrombosis in a model of T1DM.

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Superoxide Dismutase 2 is dispensable for platelet function

Cited by 21 publications

References 33 publications

Nox2 NADPH oxidase is dispensable for platelet activation or arterial thrombosis in mice

Nox2 NADPH oxidase is dispensable for platelet activation or arterial thrombosis in mice

ROS in Platelet Biology: Functional Aspects and Methodological Insights

Glucose Metabolism Is Required for Platelet Hyperactivation in a Murine Model of Type 1 Diabetes

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