Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease

Reiter, Christopher D.; Wang, Xunde; Tanus‐Santos, José Eduardo; Hogg, Neil; Cannon, Richard O.; Schechter, Alan N.; Gladwin, Mark T.

doi:10.1038/nm1202-799

Cited by 1,083 publications

(1,080 citation statements)

References 45 publications

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“…This pattern was confirmed whether using TBARS method in the presence of desferal and BHT (Figure 2A), or using using 8-isoprostane determination in the liver tissue (see Figure 2B). In BERK mice as in human SCD, chronic depletion of arginine levels, reduced NO production and NO consumption by the plasma heme as reported before [11,24,26,35] may all contribute to a proinflammatory milieu and in greater LPO levels.…”

Section: Effect Of Disease Severitymentioning

confidence: 53%

“…Since L-NAME competes with endogenous arginine to reduce NO production, the marked increase in oxidative stress in both C57BL and NY1DD mice following L-NAME treatment is in accord with the inflammatory effects of reduced NO availability that characterizes SCD [16,35]. This was evident by not only increased LPO levels, but also a marked decrease in various antioxidants, i.e., GSH, SOD, catalase and GPx (see Table 1).…”

Section: Inflammatory Effect Of L-namementioning

confidence: 82%

“…Although NY1DD mice do not exhibit hemolysis, BERK mice show more than 2-fold increase in cell-free plasma heme compared with controls [16] that may result in consumption/ inactivation of NO by ferrous hemoglobin as described [35]. In addition, transient vasoocclusive events in BERK mice, caused by intravascular sickling, will result in reperfusion injury and oxidant generation contributing to NO consumption by O 2 •− [3,16].…”

Section: Protective Effect Of Argininementioning

confidence: 91%

“…Induction of mitochondrial peroxynitrite by sodium nitroprusside, an NO donor, can also induce GSH synthesis [19]. In fact, BERK mice show several-fold increase in nitrotyrosine [16], probably because initial higher production of NO in this model and in human SCD is followed by consumption of NO by oxygen radicals and plasma heme that could lead to increased metabolism and depletion of arginine substrate [25,35].…”

Section: Effect Of Disease Severitymentioning

confidence: 94%

“…In SCD, growing evidence shows reduced bioavailability of nitric oxide (NO), probably due to consumption of NO by free oxygen radicals, and/or by cell free-plasma heme as a result of hemolysis [3,35]. In SCD and sickle mouse models, a preponderance of recent observations shows depleted levels of L-arginine, a substrate for NO, and NO metabolites (NOx) [24,25,36].…”

Section: Introductionmentioning

confidence: 99%

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

Dasgupta

Hebbel

Kaul

2006

Free Radical Biology and Medicine

129

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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Section: Effect Of Disease Severitymentioning

confidence: 53%

Section: Inflammatory Effect Of L-namementioning

confidence: 82%

Section: Protective Effect Of Argininementioning

confidence: 91%

Section: Effect Of Disease Severitymentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Dasgupta

Hebbel

Kaul

2006

Free Radical Biology and Medicine

129

101

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Evolution of Novel Small-Molecule Therapeutics Targeting Sickle Cell Vasculopathy

Kato

Gladwin

2008

JAMA

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A 34-year-old African American woman with sickle cell disease and history of relatively severe hemolysis, chronic leg ulcers, and mild pulmonary hypertension presented with a new ischemic stroke. Recent research has suggested a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease, which features severe hemolytic anemia and leads to scavenging of nitric oxide and its biochemical precursor L-arginine. This diminished bioavailability of nitric oxide promotes a hemolysis-vascular dysfunction syndrome, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke. Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules, platelets, and the vascular protectant hemeoxygenase-1. Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase. Identification of dysregulated vascular biology pathways in sickle vasculopathy has provided a focus for new clinical trials for therapeutic intervention, including inhaled nitric oxide, sodium nitrite, L-arginine, Corresponding Author: Gregory J. Kato, MD, Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Dr, MSC 1476, Bldg 10-CRC, Room 5-5140, Bethesda, MD 20892-1476 Financial Disclosures: Dr Gladwin reports being named as a coinventor on a National Institutes of Health (NIH) government patent application for the therapeutic use of nitrite salts for cardiovascular indications and on a second patent for a hemoglobin-based blood substitute. Dr Kato reported no disclosures. Additional Information:The patient data were collected as part of a registered clinical research protocol (clinicaltrials.gov identifier NCT00081523). The patient presented in this article reviewed its contents and consented in writing to its publication. CASE PRESENTATIONThe patient is a 34-year-old African American woman with homozygous sickle cell disease (SCD) undergoing hydroxyurea therapy for several years, with an 18-year history of leg ulceration (Figure 1). Steady-state laboratory values included hemoglobin 8.7 g/dL (35th percentile for SCD patients evaluated at the National Institutes of Health [NIH] between 1999[NIH] between -2003, reticulocyte count 370×10 3 /μL (83rd percentile), and serum lactate dehydrogenase (LDH) highly elevated at 486 U/L (83rd percentile). The ratio of plasma arginine to ornithine was 0.54 (33rd percentile). The patient was found to have mild elevation of the N-terminal pro-brain natriuretic peptide (NT-proBNP) level at 177 pg/mL, and on Doppler echocardiography, a borderline high tricuspid regurgitant jet velocity of 2.5 m/s, both suggestive of mildly elevated pulmonary systolic pressures.During a subsequent hospitalization for vaso-occlusive crisis, the patient developed clinical features of encephalopathy, renal insufficiency, and pulmonary infiltrat...

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Hydroxyurea and Sickle Cell Disease

Weiner¹,

Brugnara²

2003

JAMA

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Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease

Cited by 1,083 publications

References 45 publications

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

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

Evolution of Novel Small-Molecule Therapeutics Targeting Sickle Cell Vasculopathy

Hydroxyurea and Sickle Cell Disease

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