Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice

Wood, Katherine C.; Hebbel, Robert P.; Granger, D. Neil

doi:10.1096/fj.04-3218fje

Cited by 111 publications

(94 citation statements)

References 37 publications

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“…Leukocyte-endothelial and platelet-endothelial cell adhesion was observed in the cerebral microvasculature of wild-type (WT), SOD1 transgenic (SOD1-TgN), and gp91phox-deficient mice transplanted with bone marrow from sickle cell transgenic mice. NADPH oxidase inactivation was as effective as SOD overexpression in abolishing both the leukocyte and platelet adhesion responses typically observed in SCD mice (109).…”

Section: Increased Vascular and Tissue Oxidant Generationmentioning

confidence: 91%

“…Superoxide derived from endothelial cell NADPH oxidase also mediates microvascular dysfunction in sickle cell transgenic mice (109). Vascular endothelial cells contain all requisite phox proteins and the low molecular weight GTP binding protein of the multicomponent phagocytic NADPH oxidase system (134).…”

Section: Increased Vascular and Tissue Oxidant Generationmentioning

confidence: 99%

“…An increase in the production of superoxide uncoupled NO synthases (NOS) has also been implicated in the pathogenesis of SCD (109,121). Nitric oxide is synthesized by a family of NOS enzymes that have a C-terminal reductase and an N-terminal oxygenase domain (93).…”

Section: Increased Vascular and Tissue Oxidant Generationmentioning

confidence: 99%

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Redox-dependent impairment of vascular function in sickle cell disease

Aslan

Freeman

2007

Free Radical Biology and Medicine

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The vascular pathophysiology of sickle cell disease (SCD) is influenced by many factors including adhesiveness of red and white blood cells to endothelium, increased coagulation and homeostatic perturbation. The vascular endothelium is central to disease pathogenesis because it displays adhesion molecules for blood cells, balances procoagulant and anticoagulant properties of the vessel wall and regulates vascular homeostasis by synthesizing vasoconstricting and vasodilating substances. Occurrence of intermittent vascular occlusion in SCD leads to reperfusion injury associated with granulocyte accumulation and enhanced production of reactive oxygen species. The participation of nitric oxide (NO) in oxidative reactions causes a reduction in NO bioavailability and contributes to vascular dysfunction in SCD. Therapeutic strategies designed to counteract endothelial, inflammatory and oxidative abnormalities may reduce the frequency of hospitalization, blood transfusion, the incidence of pain and the occurrence of acute chest syndrome and pulmonary hypertension in patients with SCD.

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Section: Increased Vascular and Tissue Oxidant Generationmentioning

confidence: 91%

Section: Increased Vascular and Tissue Oxidant Generationmentioning

confidence: 99%

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Redox-dependent impairment of vascular function in sickle cell disease

Aslan

Freeman

2007

Free Radical Biology and Medicine

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“…22 Recent studies have suggested a role for vascular NADPH oxidase in aberrant superoxide-mediated NO scavenging in the sickle cell cerebral vasculature. 23 It is increasingly clear from these studies that plasma hemoglobin-mediated and oxygen free radical-mediated consumption of NO produces a state of resistance to NO in patients with sickle cell disease. During intravascular hemolysis, the diffusional barriers that limit NO reactions with hemoglobin are disrupted and the cell-free plasma hemoglobin destroys NO at a rate 1000-fold faster than intra-erythrocytic hemoglobin.…”

Section: Endothelial Dysfunction In Sickle Cell Disease: a Unique Stamentioning

confidence: 99%

Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia

Gladwin

Kato²

2005

Hematology

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Medical advances in the management of patients with sickle cell disease, thalassemia, and other hemolytic anemias have led to significant increases in life expectancy. Improved public health, neonatal screening, parental and patient education, advances in red cell transfusion medicine, iron chelation therapy, penicillin prophylaxis for children, pneumococcal immunization, and hydroxyurea therapy have all likely contributed to this effect on longevity. 1,2 Importantly, as a generation of patients with sickle cell disease and thalassemia ages, new chronic complications of these hemoglobinopathies develop. In this context, pulmonary hypertension is emerging as one of the leading causes of morbidity and mortality in adult sickle cell and thalassemia patients, and likely in patients with other hemolytic anemias. A common feature of both sickle cell disease and thalassemia is intravascular hemolysis and chronic anemia. Recent data suggest that chronic intravascular hemolysis is associated with a state of endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability, pro-oxidant and pro-inflammatory stress and coagulopathy, leading to vasomotor instability and ultimately producing a proliferative vasculopathy, a hallmark of which is the development of pulmonary hypertension in adulthood. 3-5 In conclusion, pulmonary hypertension is common in patients with hereditary hemolytic anemias and is associated with a high risk of death in patients with sickle cell disease. New therapies targeting this vasculopathy and aimed at normalizing the vasodilator:vasoconstrictor balance are discussed.

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“…However, there is no definitive data on the status of antioxidant enzyme and lipid peroxidation according to the disease severity, as well as on the effect of NO replenishment. Among the likely sources of O 2 •− in SCD are plasma membrane NADPH oxidase [12,44], enzyme NO synthase due to depleted substrate arginine [40] and increased plasma xanthine oxidase (XO) activity [3,41].…”

Section: Introductionmentioning

confidence: 99%

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

Dasgupta

Hebbel

Kaul

2006

Free Radical Biology and Medicine

127

101

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Sickle cell disease (SCD) is characterized by reperfusion injury and chronic oxidative stress. Oxidative stress and hemolysis in SCD result in inactivation of nitric oxide (NO) and depleted arginine levels. We hypothesized that augmenting NO production by arginine supplementation will reduce oxidative stress in SCD. To this end, we measured the effect of arginine (5% in mouse chow) on NO metabolites (NOx), lipid peroxidation (LPO) and selected antioxidants in transgenic sickle mouse models. Untreated transgenic sickle (NY1DD) mice (expressing ~75% β S -globin of all β-globins; mild pathology) and knockout sickle (BERK) mice (expressing exclusively hemoglobin S; severe pathology) showed reduced NOx levels and significant increases in the liver LPO compared with C57BL mice, with BERK mice showing maximal LPO increase in accordance with the disease severity. This was accompanied by reduced activity of antioxidants (glutathione [GSH], total superoxide dismutase [SOD], catalase and glutathione peroxidase [GPx]). However, GSH levels in BERK were higher than in NY1DD mice indicating a protective response to greater oxidative stress. Importantly, dietary arginine significantly increased NOx levels, reduced LPO and increased antioxidants in both sickle mouse models. In contrast, L-NAME, a potent non-selective NOS inhibitor, worsened the oxidative stress in NY1DD mice. Thus, attenuating effect of arginine on oxidative stress in SCD mice suggests its potential application in the management of this disease.

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Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice

Cited by 111 publications

References 37 publications

Redox-dependent impairment of vascular function in sickle cell disease

Redox-dependent impairment of vascular function in sickle cell disease

Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

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