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

Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 11/2004; 114(8):1136-45. DOI: 10.1172/JCI21633
Source: PubMed


In sickle cell disease, intravascular sickling and attendant flow abnormalities underlie the chronic inflammation and vascular endothelial abnormalities. However, the relationship between sickling and vascular tone is not well understood. We hypothesized that sickling-induced vaso-occlusive events and attendant oxidative stress will affect microvascular regulatory mechanisms. In the present studies, we have examined whether microvascular abnormalities expressed in sickle transgenic-knockout Berkeley (BERK) mice (which express exclusively human alpha- and beta(S)-globins with <1% gamma-globin levels) are amenable to correction with increased levels of antisickling fetal hemoglobin (HbF). In BERK mice, sickling, increased oxidative stress, and hemolytic anemia are accompanied by vasodilation, compensatory increases in eNOS and COX-2, and attenuated vascular responses to NO-mediated vasoactive stimuli and norepinephrine. The hypotension and vasodilation (required for adequate oxygen delivery in the face of chronic anemia) are mediated by non-NO vasodilators (i.e., prostacyclin) as evidenced by induction of COX-2. In BERK mice, the resistance to NO-mediated vasodilators is associated with increased oxidative stress and hemolytic rate, and in BERK + gamma mice (expressing 20% HbF), an improved response to these stimuli is associated with reduced oxidative stress and hemolytic rate. Furthermore, BERK + gamma mice show normalization of vessel diameters, and eNOS and COX-2 expression. These results demonstrate a strong relationship between sickling and microvascular function in sickle cell disease.

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Available from: Mary Fabry, Oct 09, 2015
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    • "Currently, hydroxycarbamide or hydroxyurea (HU) is the only disease-modifying therapy approved for SCD, wherein the increased synthesis of Hb Fetal (HbF) is the main effect of this drug [98]. The augmented Hb F expression reduces several oxidative stress biomarkers and NO scavenging both in sickle cell mice and SCD patients [58] [86] [99] [100]. Other results also showed that increasing concentrations of Hb F, a protective effect of HU, is directly proportional to the increase in CAT activity and GSH levels, and decreased lipid peroxidation [58] [99]. "
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    ABSTRACT: Erythrocytes have an environment of continuous prooxidant generation due to hemoglobin (Hb) presence that represents an additional and quantitatively significant source of superoxide (O2(•-)) generation in biological systems. In order to counteract oxidative stress, erythrocytes have a self-sustaining antioxidant defense system. Therefore, red blood cells (RBCs) uniquely function to protect Hb via a selective barrier allowing gaseous and other ligand transport as well as providing antioxidant protection not only to themselves but also to other tissues and organs in the body. HbS molecules suffer repeated polymerization/depolymerization generating greater extent of reactive oxygen species (ROS), which can lead to a cyclic cascade characterized by blood cell adhesion, hemolysis, vaso-occlusion, and ischemia-reperfusion injury. In other words, sickle cell disease is intimately linked to a pathophysiologic condition of multiple sources of prooxidant processes with consequent chronic and systemic oxidative stress. For this reason, newer therapeutic agents that can target oxidative stress may constitute valuable means for preventing or delaying the development of organ complications.
    Free Radical Biology and Medicine 08/2013; 65. DOI:10.1016/j.freeradbiomed.2013.08.181 · 5.74 Impact Factor
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    • "et al 2006) A major risk factor for the development of PH is chronic haemolytic anaemia. Despite the robust basic and epidemiological data suggesting that an increased TRV is common and associated with high mortality in patients with SCD (Ataga, et al 2006, Dasgupta, et al 2010, De Castro, et al 2008, Frei, et al 2008, Gladwin, et al 2004, Hill, et al 2010, Hsu, et al 2007, Kato, et al 2006, Kaul, et al 2004, Machado, et al 2006, Meyer, et al 2010, Minniti, et al 2009, Naoman, et al 2009, Nolan, et al 2006, Nolan, et al 2005, Onyekwere, et al 2008, Reiter, et al 2002, Voskaridou, et al 2007, Yeo, et al 2007, Yeo, et al 2009), the importance of this complication and the mechanistic link to haemolytic anaemia has been recently challenged.(Bunn, et al, 2010) In order to further test our data-driven hypothesis we obtained frozen plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD), for analysis of a biomarker, NT-proBNP, which is elevated in the setting of pulmonary arterial and venous hypertension or left-sided heart disease. "
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    ABSTRACT: Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160ng/l was present in 27·6% of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0·001), high lactate dehydrogenase (P<0·001), and high total bilirubin levels (P<0·007). A NT-proBNP level ≥160ng/l was an independent predictor of mortality (RR 6·24, 95% CI 2·9-13·3, P<0·0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population.
    British Journal of Haematology 06/2011; 154(4):512-20. DOI:10.1111/j.1365-2141.2011.08777.x · 4.71 Impact Factor
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    • "Finally, increased HbF content in sickle red cells prolongs red cell survival (Franco et al, 2006). The attendant reduction in haemolysis is likely to improve microvascular function and reduce chronic organ damage (Kaul et al, 2004). "
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    ABSTRACT: While supportive care remains the best option for most well children with sickle cell disease (SCD), increasing awareness of early signs of chronic organ damage in childhood has focused attention on therapy which modulates the natural history of the disease. Since cure by stem cell transplantation is only feasible for a minority and gene therapy remains developmental, pharmacological modification by Haemoglobin F (HbF)-inducers, is the most widely used approach in SCD. Currently, the only HbF modulator with a clear place in the management of childhood SCD is hydroxycarbamide for which the main indications are frequent painful crises and recurrent acute chest syndrome. In the majority of SCD children treated with hydroxycarbamide there is clear evidence of clinical benefit and the drug is well tolerated. The main disadvantages are the need for frequent monitoring and uncertainity about long-term risks of carcinogenicity and impaired fertility, although these risks appear to be very low. The role of hydroxycarbamide in sickle-associated central nervous system disease remains to be established. Decitabine and butyrate derivatives show some promise although robust data in children with SCD are lacking. A number of other drugs are currently under investigation for their effects on HbF production including thalidomide and lenolidamide.
    British Journal of Haematology 12/2008; 144(3):308-16. DOI:10.1111/j.1365-2141.2008.07482.x · 4.71 Impact Factor
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