High expression of human beta S- and alpha-globins in transgenic mice: hemoglobin composition and hematological consequences.

Fabry, Mary E.; Nagel, Ronald L.; Pachnis, Agathe; Suzuka, Sandra M.; Costantini, Frank

doi:10.1073/pnas.89.24.12150

Cited by 105 publications

(88 citation statements)

References 24 publications

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“…The b S/S-Antilles mice are homozygous for deletion of the mouse b major globin locus [b MDD ] and express human a, b S , and b S-Antilles globin transgenes. These mice were produced by breeding a H b S [b MDD ] mice [39] into a mouse line expressing human b S-Antilles on the mouse homozygous b major deletional background [35]. b S-Antilles contains, in addition to the b S mutation at b6, a second mutation at b23 (Val!Ile).…”

Section: Materials and Methods Micementioning

confidence: 99%

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

et al. 2004

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Vascular inflammation, secondary to ischemia-reperfusion injury, may play an essential role in vaso-occlusion in sickle cell disease (SCD). To investigate this hypothesis, dorsal skin fold chambers (DSFCs) were implanted on normal and transgenic sickle mice expressing human a and b s /b s-Antilles globin chains. Microvessels in the DSFC were visualized by intravital microscopy at baseline in ambient air and after exposure to hypoxia-reoxygenation. The mean venule diameter decreased 9% (P < 0.01) in sickle mice after hypoxia-reoxygenation but remained constant in normal mice. The mean RBC velocity and wall shear rate decreased 55% (P < 0.001) in sickle but not normal mice after hypoxia-reoxygenation. None of the venules in normal mice became static at any time during hypoxia-reoxygenation; however, after 1 hr of hypoxia and 1 hr of reoxygenation, 11.9% of the venules in sickle mice became static (P < 0.001). After 1 hr of hypoxia and 4 hr of reoxygenation, most of the stasis had resolved; only 3.6% of the subcutaneous venules in sickle mice remained static (P = 0.01). All of the venules were flowing again after 24 hr of reoxygenation. Vascular stasis could not be induced in the subcutaneous venules of sickle mice by tumor necrosis factor alpha (TNF-a). Leukocyte rolling flux and firm adhesion, manifestations of vascular inflammation, were significantly higher at baseline in sickle mice compared to normal (P < 0.01) and increased 3-fold in sickle (P < 0.01), but not in normal mice, after hypoxia-reoxygenation. Plugs of adherent leukocytes were seen at bifurcations at the beginning of static venules. Misshapen RBCs were also seen in subcutaneous venules. Am.

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Section: Materials and Methods Micementioning

confidence: 99%

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

et al. 2004

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“…In NY1DD mice, β S -globin forms symmetrical tetramers with human α-globin (42%) and with mouse α-globin (~30%). In these mice, the total β S -globin levels are ~ 75% β S of all β-globins [8]. NY1DD mice show mild pathology, but exhibit multiple organ damage [7].…”

Section: Transgenic Micementioning

confidence: 99%

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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“…These mice express 100% human α, 79% human β S , and 21% human γ. Group 3 animals (NY1DD or α H β S αβ DD ) were generated as described [15]. These mice have a single copy of the NY1 transgene (co-integrated LCRα and LCRβ S ) [15] and are homozygous for the mouse β major deletion [18].…”

Section: Transgenic Micementioning

confidence: 99%

“…The presence of γ has two effects: 1) as a beta-like globin it reduces the thalassemia-like behavior in the BERK mouse red cell and 2) it reduces polymer formation. A less severe sickle transgenic model (NY1DD) that has been extensively characterized [15] did not result in significantly increased heme degradation. However, NY1 mice with homozygous knockouts of both mouse α-and β-globin, combined with γM (NY1KO-γM that resulted in expression of about 20% HbF, Table 1) resulted in a significant increase in heme degradation, similar to that of BERK mice.…”

Section: Heme Degradation Products In Sickle Transgenic Micementioning

confidence: 99%

“…Transgenic mouse models for pathological hemoglobins are useful experimental tools for testing experimental hypothesis and interventions. Transgenic mice expressing HbS [14][15][16] and HbC [17] were generated by inserting human transgenes that code for human α-and mutant β-chains, and by knocking out murine α-and β-globins. The thalassemia model used here is the result of a homozygous deletion of murine β major [18].…”

Section: Introductionmentioning

confidence: 99%

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Heme degradation and oxidative stress in murine models for hemoglobinopathies: Thalassemia, sickle cell disease and hemoglobin C disease

Nagababu

Fabry

Nagel

et al. 2008

Blood Cells, Molecules, and Diseases

103

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Red blood cells with abnormal hemoglobins (Hb) are frequently associated with increased hemoglobin autoxidation, accumulation of iron in membranes, increased membrane damage and a shorter red cell life span. The mechanisms for many of these changes have not been elucidated. We have shown in our previous studies that hydrogen peroxide formed in association with hemoglobin autoxidation reacts with hemoglobin and initiates a cascade of reactions that results in heme degradation with the formation of two fluorescent emission bands and the release of iron. Heme degradation was assessed by measuring the fluorescent band at ex 321 nm. A 5.6 fold increase in fluorescence was found in red cells from sickle transgenic mice that expressed exclusively human globins when compared to red cells from control mice. When sickle transgenic mice co-express the γM transgene, that expresses HbF and inhibits polymerization, heme degradation is decreased. Mice expressing exclusively hemoglobin C had a 6.9 fold increase in fluorescence compared to control. Heme degradation was also increased 3.5 fold in β-thalassemic mice generated by deletion of murine β major . Membrane bound IgG and red cell metHb were highly correlated with the intensity of the fluorescent heme degradation band. These results suggest that degradation of the heme moiety in intact hemoglobin and/or degradation of free heme by peroxides are higher in pathological RBCs. Concomitant release of iron appears to be responsible for the membrane damage that leads to IgG binding and the removal of red cells from circulation.

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High expression of human beta S- and alpha-globins in transgenic mice: hemoglobin composition and hematological consequences.

Cited by 105 publications

References 24 publications

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

Microvascular blood flow and stasis in transgenic sickle mice: Utility of a dorsal skin fold chamber for intravital microscopy

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

Heme degradation and oxidative stress in murine models for hemoglobinopathies: Thalassemia, sickle cell disease and hemoglobin C disease

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