Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice

Kaul, Dhananjay K.; Liu, Xiao-du; Chang, Hee-Yoon; Nagel, Ronald L.; Fabry, Mary E.

doi:10.1172/jci200421633

Cited by 96 publications

(101 citation statements)

References 45 publications

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“…The disease severity in the context of this study refers to the sickling ability of red cells in NY1DD (mild pathology) and BERK mice (severe pathology) which is proportional to the percent of β S -globin synthesis in these models (see Methods). BERK mice, expressing exclusively human α-and β S -globins, show maximal intravascular sickling, hence frequent transient vaso-occlusive events [16,33,39]. Importantly, we show that the replenishment of NO by dietary arginine results in significant decrease in oxidative stress in these transgenic sickle models.…”

Section: Discussionmentioning

confidence: 62%

“…GSH is initially depleted by ischemia/reperfusion and by inflammatory cytokines (e.g., TNF-α) but shows a rebound as an adaptive response to oxidative stress [28,34]. The higher GSH activity in BERK mice as compared with less severe NY1DD mice may be a protective response to a greater oxidative stress in this model caused by recurring ischemic-reperfusion events, increased levels of inflammatory cytokines and higher levels of protein nitration [16] that are known to enhance GSH synthesis [34]. GSH effectively scavenges reactive oxygen species directly and indirectly via enzymatic reactions [45].…”

Section: Effect Of Disease Severitymentioning

confidence: 84%

“…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: 95%

“…BERK mice exhibit several features of human SCD, i.e., hemolysis, reticulocytosis, low hematocrit and extensive multiple organ damage [33,37]. Hemolytic anemia in BERK mice is associated with significantly low systemic hematocrit, i.e., 28.7 ± 4.0 (P<0.00001 vs. controls) [16]. Globin composition was determined by denaturing HPLC as described [9].…”

Section: Transgenic Micementioning

confidence: 99%

“…Depleted NO production in a transgenic-knockout (BERK) model is associated with increased tyrosine nitration [16], suggesting that hemolysis in this model may trigger the reported hemin-mediated nitrotyrosine formation in the presence of nitrite and hydrogen peroxide (H 2 O 2 ) [38]. L-arginine (a substrate for NO) and several NO donors can decrease the damage resulting from post-ischemic reperfusion [14].…”

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: Discussionmentioning

confidence: 62%

Section: Effect Of Disease Severitymentioning

confidence: 84%

Section: Effect Of Disease Severitymentioning

confidence: 95%

Section: Transgenic Micementioning

confidence: 99%

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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Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis

Gladwin¹

2011

JAMA

207

139

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Context Inhaled nitric oxide (NO) has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC). Objective To determine whether inhaled NO gas reduces the duration of painful crisis in patients with SCD who present to the emergency room or hospital for care. Design, Setting and Participants Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled NO gas versus inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004 and December 22, 2008. The primary endpoint was the time to resolution of painful crisis, defined by: 1) freedom from parenteral opioid use for 5 hours; 2) pain relief as assessed by visual analog pain scale scores ≤ 6 cm; 3) ability to walk; and 4) patient and family’s decision, with physician consensus, that the remaining pain could be managed at home. Intervention Inhaled NO gas versus inhaled nitrogen placebo. Results There was no significant change in the primary endpoint between the NO and the placebo groups, with a median time to resolution of crisis of 73.0 hours (95% CI: 46.0–91.0) and 65.5 hours (95% CI: 48.1–84.0), respectively (P=.87). There were no significant differences in secondary outcome measures, including length of hospitalization, VAS scores, cumulative opioid usage and the rate of acute chest syndrome. Inhaled NO was well tolerated with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed compliance and randomization, but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite. Conclusions Among patients with SCD hospitalized with VOC, the use of inhaled NO compared with placebo did not improve time to crisis resolution.

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The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin

Rother¹,

Bell²,

Hillmen³

et al. 2005

JAMA

1,400

1,177

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Context The efficient sequestration of hemoglobin by the red blood cell membrane and the presence of multiple hemoglobin clearance mechanisms suggest a critical need to prevent the buildup of this molecule in the plasma. A growing list of clinical manifestations attributed to hemoglobin release in a variety of acquired and iatrogenic hemolytic disorders suggests that hemolysis and hemoglobinemia should be considered as a novel mechanism of human disease. Evidence Acquisition Pertinent scientific literature databases and references were searched through October 2004 using terms that encompassed various aspects of hemolysis, hemoglobin preparations, clinical symptoms associated with plasma hemoglobin, nitric oxide in hemolysis, anemia, pulmonary hypertension, paroxysmal nocturnal hemoglobinuria, and sickle-cell disease. Evidence Synthesis Hemoglobin is released into the plasma from the erythrocyte during intravascular hemolysis in hereditary, acquired, and iatrogenic hemolytic conditions. When the capacity of protective hemoglobin-scavenging mechanisms has been saturated, levels of cell-free hemoglobin increase in the plasma, resulting in the consumption of nitric oxide and clinical sequelae. Nitric oxide plays a major role in vascular homeostasis and has been shown to be a critical regulator of basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion molecule expression, and platelet activation and aggregation. Thus, clinical consequences of excessive cell-free plasma hemoglobin levels during intravascular hemolysis or the administration of hemoglobin preparations include dystonias involving the gastrointestinal, cardiovascular, pulmonary, and urogenital systems, as well as clotting disorders. Many of the clinical sequelae of intravascular hemolysis in a prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria, are readily explained by hemoglobin-mediated nitric oxide scavenging. Conclusion A growing body of evidence supports the existence of a novel mechanism of human disease, namely, hemolysis-associated smooth muscle dystonia, vasculopathy, and endothelial dysfunction.

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Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice

Cited by 96 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

Nitric Oxide for Inhalation in the Acute Treatment of Sickle Cell Pain Crisis

The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin

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